tbuckley/cabot-search huggingface dataset:
RUNX2 is stabilised by TAZ and drives pulmonary artery calcification and lung vascular remodelling in pulmonary hypertension due to left heart disease
Authors: Shao-Fei Liu, Mariya M Kucherenko, Pengchao Sang, Qiuhua Li, Juquan Yao, Netra Nambiar Veetil, Tara Gransar, Ioana Alesutan, Jakob Voelkl, Gabriela Salinas, Jana Grune, Szandor Simmons, Christoph Knosalla, Wolfgang M Kuebler
Journal: European Respiratory Journal (2024)

Calcification is common in chronic vascular disease, yet its role in pulmonary hypertension due to left heart disease is unknown. Here, we probed for the role of runt-related transcription factor-2 (RUNX2), a master transcription factor in osteogenesis, and its regulation by the HIPPO pathway transcriptional coactivator with PDZ-binding motif (TAZ) in the osteogenic reprogramming of pulmonary artery smooth muscle cells and vascular calcification in patients with pulmonary hypertension due to left heart disease. We similarly examined its role using an established rat model of pulmonary hypertension due to left heart disease induced by supracoronary aortic banding.
Update on Pediatric Surveillance Recommendations for <i>PTEN</i> Hamartoma Tumor Syndrome, <i>DICER1-</i>Related Tumor Predisposition, and Tuberous Sclerosis Complex
Authors: Kris Ann P. Schultz, Suzanne P. MacFarland, Melissa R. Perrino, Sarah G. Mitchell, Junne Kamihara, Alexander T. Nelson, Paige H.R. Mallinger, Jack J. Brzezinski, Kara N. Maxwell, Emma R. Woodward, Bailey Gallinger, Sun Young Kim, Mary-Louise C. Greer, Kami Wolfe. Schneider, Sarah R. Scollon, Anirban Das, Jonathan D. Wasserman, Charis Eng, David Malkin, William D. Foulkes, Orli Michaeli, Andrew J. Bauer, Douglas R. Stewart
Journal: Clinical Cancer Research (2024)

Abstract PTEN hamartoma tumor syndrome (PHTS), DICER1-related tumor predisposition (DICER1) and tuberous sclerosis complex (TSC) are rare conditions which each increase risk for distinct spectra of benign and malignant neoplasms throughout childhood and adulthood. Surveillance considerations for each of these conditions focus on patient and family education, early detection and multidisciplinary care. In this manuscript, we present updated surveillance recommendations and considerations for children and adolescents with PHTS, DICER1 and TSC and provide suggestions for further research in each of these conditions.
Pericancerous cross-presentation to cytotoxic T lymphocytes impairs immunotherapeutic efficacy in hepatocellular carcinoma
Authors: Chun-Xiang Huang, Xiang-Ming Lao, Xu-Yan Wang, Yi-Zheng Ren, Yi-Tong Lu, Wei Shi, Ying-Zhe Wang, Cai-Yuan Wu, Li Xu, Min-Shan Chen, Qiang Gao, Lianxin Liu, Yuan Wei, Dong-Ming Kuang
Journal: Cancer Cell (2024)
Systematic review of immune checkpoint inhibitor-related gastrointestinal, hepatobiliary, and pancreatic adverse events
Authors: Malek Shatila, Hao Chi Zhang, Anusha Shirwaikar Thomas, Antonio Pizuorno Machado, Sidra Naz, Nitish Mittal, Christine Catinis, Krishnavathana Varatharajalu, Carolina Colli Cruz, Eric Lu, Deanna Wu, Julie R Brahmer, Franck Carbonnel, Stephen B Hanauer, Bret Lashner, Bryan Schneider, John A Thompson, Michel Obeid, David P Farris, Yinghong Wang
Journal: Journal for ImmunoTherapy of Cancer (2024)

Gastrointestinal immune-related adverse events (GI irAEs) are common manifestations of immune checkpoint inhibitor (ICI) toxicity. We present a comprehensive systematic review of the incidence, management, and clinical course of irAEs across the entire GI system, including the luminal GI tract, liver, and pancreas. MEDLINE, Embase, Web of Science Core Collection, and Cochrane Library were used to conduct this review. All studies pertaining to GI irAEs were included. Both abstracts and full manuscripts were eligible if they included human subjects and were written in the English language. Articles not available in English, animal studies, or research not specific to GI toxicity of immunotherapy were excluded. We excluded certain article types depending on whether stronger evidence was available in the literature for a specific toxicity, for example, if prospective studies were available on a topic, retrospective studies and case reports were excluded. We extracted a final 166 articles for our review and followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines for data reporting. Risk of bias tools were not used to evaluate the extracted studies given the narrative nature of this manuscript, but each study was critically appraised by the manuscript writer. We detail the incidence, presentation, evaluation, management, and outcomes of the various GI toxicities that may arise with ICI therapy. Specifically, we discuss the characteristics of upper GI toxicity (esophagitis and gastroenteritis), lower GI toxicity (colitis), hepatobiliary inflammation, pancreatitis, and rarer forms of GI toxicity. We hope this review serves as a useful and accessible clinical tool that helps physicians familiarize themselves with the nuances of gastrointestinal/hepatic/pancreatic ICI toxicity diagnosis and management.
DLL4-targeted CAR-T therapy sensitizes neoadjuvant chemotherapy via eliminating cancer stem cells and reshaping immune microenvironment in HER2<sup>+</sup>breast cancer
Authors: Jingrui Yan, Yongjie Xie, Ziyun Liu, Yanfang Yang, Tianxing Zhou
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background Neoadjuvant therapy with trastuzumab, pertuzumab and paclitaxel (THP) has significantly improved the prognosis of patients with human epidermal growth factor receptor 2 (HER2) + breast cancer (BC). However, there remains a subset of non-responsive patients. Thus, this study sought to identify key regulators of THP neoadjuvant therapy resistance and potential targets to sensitize sensitivity. Methods The Cancer Genome Atlas database, Gene Expression Omnibus and membrane protein database were used to identify the key regulator of THP neoadjuvant resistance. The biological functions and mechanisms of delta-like 4 proteins (DLL4) in THP therapy resistance were investigated in vitro and in vivo using the bioinformatic analysis, multiplex immunofluorescence, flow cytometry, sphere formation assays and chromatin immunoprecipitation, etc. Furthermore, DLL4-targeted chimeric antigen receptor (CAR)-T cells were established to sensitize THP therapy. Results DLL4 was identified as a key target in THP neoadjuvant therapy resistance for HER2 + BC. Mechanistically, DLL4 + tumor cells exhibited enhanced stemness and resistance to the THP neoadjuvant chemotherapy. Additionally, soluble DLL4 can split away from tumor cells and diffuse into the stroma, where it can activate the Notch signaling pathway in neutrophils, inducing the formation and release of neutrophil extracellular traps (NETs) by regulating the transcription of MPO, PDIA4 and ELANE. This led to the exclusion of lymphocyte infiltration, thereby enhancing therapy resistance. What is more, we designed a DLL4-targeted CAR-T to eliminate DLL4 + tumor cells and reverse the resistant status. Conclusions Our study revealed novel functions of DLL4 in cell stemness and immune infiltration, including NET formation and T cell exclusion, which collectively contributed to THP neoadjuvant therapy resistance in HER2 + BC. Furthermore, we provided a CAR-T-based therapy to sensitize the THP neoadjuvant therapy.
Calcium phosphate nanoclusters modify periodontium remodeling and minimize orthodontic relapse
Authors: Darnell L Cuylear, Moyu L Fu, Justin C Chau, David Bulkley, Bhushan Kharbikar, Galateia J Kazakia, Andrew H Jheon, Stefan Habelitz, Sunil D Kapila, Tejal A Desai
Journal: Biomaterials (2024)

Orthodontic relapse is one of the most prevalent concerns of orthodontic therapy. Relapse results in patients' teeth reverting towards their pretreatment positions, which increases the susceptibility to functional problems, dental disease, and substantially increases the financial burden for retreatment. This phenomenon is thought to be induced by rapid remodeling of the periodontal ligament (PDL) in the early stages and poor bone quality in the later stages. Current therapies including fixed or removable retainers and fiberotomies have limitations with patient compliance and invasiveness. Approaches using biocompatible biomaterials, such as calcium phosphate polymer-induced liquid precursors (PILP), are an ideal translational approach for minimizing orthodontic relapse. Here, post-orthodontic relapse is reduced after a single injection of high concentration PILP (HC-PILP) nanoclusters by altering PDL remodeling in the early stage of relapse and improving trabecular bone quality in the later stage. HC-PILP nanoclusters are achieved by using high molecular weight poly aspartic acid (PASP, 14 kDa) and poly acrylic acid (PAA, 450 kDa), which resulted in a stable solution of high calcium and phosphate concentrations without premature precipitation. In vitro results show that HC-PILP nanoclusters prevented collagen type-I mineralization, which is essential for the tooth-PDL-bone interphase. In vivo experiments show that the HC-PILP nanoclusters minimize relapse and improve the trabecular bone quality in the late stages of relapse. Interestingly, HC-PILP nanoclusters also altered the remodeling of the PDL collagen during the early stages of relapse. Further in vitro experiments showed that HC-PILP nanoclusters alter the fibrillogenesis of collagen type-I by impacting the protein secondary structure and forming aggregates. These findings propose a new approach for treating orthodontic relapse and provide additional insight into the PILP nanocluster's structure and properties on collagenous structure repair.
Systemic chemokine-modulatory regimen combined with neoadjuvant chemotherapy in patients with triple-negative breast cancer
Authors: Shipra Gandhi, Ronald T Slomba, Cayla Janes, Victoria Fitzpatrick, Janine Miller, Kristopher Attwood, Giorgio Ioannou, Sinem Ozbey, Igor De Souza, Vladimir Roudko, Prasanna Kumar, Suresh Kalathil, Kathleen M Kokolus, Jianming Wang, Eduardo Cortes Gomez, Kazuaki Takabe, Stephen Edge, Jessica Young, Helen Cappuccino, Mateusz Opyrchal, Tracey O'Connor, Ellis G Levine, Sacha Gnjatic, Pawel Kalinski
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background Higher cytotoxic T lymphocyte (CTL) numbers in the tumor microenvironment (TME) predict pathologic complete response (pCR) to neoadjuvant chemotherapy (NAC) and positive long-term outcomes in triple-negative breast cancer (TNBC). pCR to NAC is achieved only in 30–40% of patients. The combination of NAC with pembrolizumab increases the pCR rate but at the cost of immune-related adverse events (irAEs). Based on these considerations, we tested if systemic infusion of the chemokine modulatory regimen (CKM; selective toll-like receptor 3 (TLR3) agonist rintatolimod, interferon (IFN)-α2b, and cyclooxygenase-2 (COX-2) inhibitor celecoxib) regimen can be safely combined with NAC to enhance intratumoral CTL numbers and NAC effectiveness. Methods Phase I study NCT04081389 evaluated nine patients with early-stage TNBC who received 3 weeks of paclitaxel with CKM (dose-escalation of IFN-α2b), followed by 9 weeks of paclitaxel alone, dose-dense doxorubicin and cyclophosphamide, and surgery. Primary and secondary endpoints were safety and clinical efficacy, respectively. Results The combination treatment was well-tolerated with no dose-limiting toxicities or irAEs. 5/9 patients achieved pCR and one patient had microinvasive disease (ypTmic). We observed elevated IFN signature and uniform decreases in CTL numbers (average 8.3-fold) in the blood of all treated patients. This was accompanied by reciprocal uniform increases in CD8β (overall 5.9-fold), CD8α/FoxP3 (2.11-fold), and CCL5 (4.73-fold) transcripts in TME, particularly pronounced in patients with pCR. Multiplex immunohistochemistry revealed selectively increased numbers of CTL (but not regulatory T cells) in both the epithelial and stromal tumor compartments and early decreases in the numbers of αSMA + vascular/stromal cells in the tumors of all pCR patients. Conclusions Combined paclitaxel/CKM regimen was safe, with desirable TME changes and preliminary indications of promising pCR+ypTmic of 66%, comparable to the combination of NAC with pembrolizumab.
FOXA1 enhances antitumor immunity via repressing interferon-induced PD-L1 expression in nasopharyngeal carcinoma
Authors: Junshang Ge, Ying Liu, Pan Chen, Zhaoyang Zeng, Guiyuan Li, Wei Xiong, Mei Yi, Bo Xiang
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background Nasopharyngeal carcinoma (NPC) is a distinct subtype of head and neck cancer which is prevalent in south of China and southeastern of Asia. Consistent activation of interferon (IFN) signaling, and impairment of T cell mediated antitumor immunity is frequent in NPC. Forkhead box A1 (FOXA1) is one of the earliest discovered pioneer factors, which can open up compact chromatin structures to facilitate the binding of other proteins to chromatin. Methods By using RNA sequencing, it was discovered that FOXA1 suppresses the activation of the interferon signaling pathway and the expression of the related interferon-responsive genes in NPC cells. The effect of FOXA1 on programmed death-ligand 1 (PD-L1) expression in C666-1 and HK1 cells under conditions with or without IFN-γ was detected through quantitative PCR (qPCR), western blot, and flow cytometry. After co-culturing T cells with IFN-γ-treated NPC cells in vitro, apoptosis of CD8 + T cells and the expression of cytotoxic cytokines were assessed by flow cytometry. The cytotoxic effects of T cells on tumor cells in nude mice were measured by tumorigenesis in nude mice and adoptive T cell therapy. The effects of IFN-γ on the expression and nuclear localization of STAT1, as well as the colocalization of FOXA1 with STAT1 were detected by immunofluorescence, qPCR, western blot, and co-immunoprecipitation experiments. Results In this study, we reported that loss of FOXA1, a pioneer factor downregulated in NPC, results in activation of IFN signaling in NPC cells. Repression of FOXA1 facilitates IFN-γ induced PD-L1 expression, whereas overexpression of FOXA1 exerts the opposite effect. Mechanistically, FOXA1 interacts with STAT1 and inhibits IRF1 expression and binding to PD-L1 promoter on IFN-γ treatment. Co-culture with FOXA1-silenced NPC cells promotes apoptosis of in vitro activated tumor-specific CD8 + T cells and reduces the expression of cytotoxic effector molecules. Furthermore, overexpression of FOXA1 increases the therapeutic efficacy of PD-L1 antibody (atezolizumab) against NPC in nude mice receiving adoptive T-cell therapy. Conclusions We demonstrated that FOXA1 prevents tumor immune evasion by inhibiting IFN-γ induced PD-L1 expression in NPC cells. Our research findings provide new insights into the immunotherapeutic biomarkers and targets for NPC, which is important for the clinical application of programmed cell death protein-1/PD-L1 antibodies in NPC.
Perspective on WHO implementation guidance on TB infection prevention and control
Authors: Onno W Akkerman, G B Migliori, Dennis Falzon, Alberto L Garcia-Basteiro, Avinash Kanchar, Olha Konstantynovska, Fusun Oner Eyuboglu, Raquel Duarte
Journal: European Respiratory Journal (2024)

<title>Extract</title> Transmission continues to drive the tuberculosis (TB) and drug-resistant TB epidemics, making infection control an essential component for public health agencies worldwide [1–3]. Transmission of TB is complex, influenced by factors linked to patient behaviour, form of disease, the exposed individual, the microbe, and the environment [3–6]. Each year more than 10 million people develop TB, over 80% of whom have pulmonary disease and over 60% are bacteriologically positive [1].
Underutilization of Influenza Antiviral Treatment Among Children and Adolescents at Higher Risk for Influenza-Associated Complications — United States, 2023–2024
Authors: Aaron M. Frutos, Haris M. Ahmad, Dawud Ujamaa, Alissa C. O’Halloran, Janet A. Englund, Eileen J. Klein, Danielle M. Zerr, Melanie Crossland, Holly Staten, Julie A. Boom, Leila C. Sahni, Natasha B. Halasa, Laura S. Stewart, Olla Hamdan, Tess Stopczynski, William Schaffner, H. Keipp Talbot, Marian G. Michaels, John V. Williams, Melissa Sutton, M. Andraya Hendrick, Mary A. Staat, Elizabeth P. Schlaudecker, Brenda L. Tesini, Christina B. Felsen, Geoffrey A. Weinberg, Peter G. Szilagyi, Bridget J. Anderson, Jemma V. Rowlands, Murtada Khalifa, Marc Martinez, Rangaraj Selvarangan, Jennifer E. Schuster, Ruth Lynfield, Melissa McMahon, Sue Kim, Val Tellez Nunez, Patricia A. Ryan, Maya L. Monroe, Yun F. Wang, Kyle P. Openo, James Meek, Kimberly Yousey-Hindes, Nisha B. Alden, Isaac Armistead, Suchitra Rao, Shua J. Chai, Pam Daily Kirley, Ariana P. Toepfer, Fatimah S. Dawood, Heidi L. Moline, Timothy M. Uyeki, Sascha Ellington, Shikha Garg, Catherine H. Bozio, Samantha M. Olson
Journal: MMWR Morbidity and Mortality Weekly Report (2024)

Annually, tens of thousands of U.S. children and adolescents are hospitalized with seasonal influenza virus infection. Both influenza vaccination and early initiation of antiviral treatment can reduce complications of influenza. Using data from two U.S. influenza surveillance networks for children and adolescents aged <18 years with medically attended, laboratory-confirmed influenza for whom antiviral treatment is recommended, the percentage who received treatment was calculated. Trends in antiviral treatment of children and adolescents hospitalized with influenza from the 2017-18 to the 2023-2024 influenza seasons were also examined. Since 2017-18, when 70%-86% of hospitalized children and adolescents with influenza received antiviral treatment, the proportion receiving treatment notably declined. Among children and adolescents with influenza during the 2023-24 season, 52%-59% of those hospitalized received antiviral treatment. During the 2023-24 season, 31% of those at higher risk for influenza complications seen in the outpatient setting in one network were prescribed antiviral treatment. These findings demonstrate that influenza antiviral treatment is underutilized among children and adolescents who could benefit from treatment. All hospitalized children and adolescents, and those at higher risk for influenza complications in the outpatient setting, should receive antiviral treatment as soon as possible for suspected or confirmed influenza.
Progress Toward Measles Elimination — Worldwide, 2000–2023
Authors: Anna A. Minta, Matt Ferrari, Sebastien Antoni, Brian Lambert, Takudzwa S. Sayi, Christopher H. Hsu, Claudia Steulet, Marta Gacic-Dobo, Paul A. Rota, Mick N. Mulders, Alice Wimmer, Anindya Sekhar Bose, Patrick O’Connor, Natasha S. Crowcroft
Journal: MMWR Morbidity and Mortality Weekly Report (2024)

Measles vaccination effectively prevents measles, a highly contagious disease that can cause severe complications and death and requires high population immunity to interrupt transmission. This report describes measles elimination progress during 2000-2023. During 2000-2023, an estimated 60.3 million measles deaths were averted by vaccination. However, despite commitment from all six World Health Organization regions to eliminate measles, no region has successfully achieved and maintained measles elimination as of the end of 2023. During the COVID-19 pandemic, estimated global coverage with the first dose of measles-containing vaccine (MCV1) declined to 81%, the lowest level since 2008. MCV1 coverage improved to 83% in 2022 but was unchanged in 2023. From 2022 to 2023, estimated measles cases increased 20% worldwide, from 8,645,000 to 10,341,000; the number of countries experiencing large or disruptive outbreaks increased from 36 to 57. Estimated measles deaths decreased 8%, from 116,800 in 2022 to 107,500 in 2023, primarily because an increased number of cases occurred in countries with lower risk for death. The stagnation in MCV1 coverage means millions of children remain unprotected, leading to increases in cases and outbreaks. Coverage with measles-containing vaccine (MCV) is lower, and measles incidence is higher, in low-income countries and countries experiencing fragile, conflict-affected, and vulnerable settings, which exacerbate inequities. Urgent and targeted efforts are needed to ensure that all children receive 2 MCV doses and that surveillance is strengthened to hasten progress toward measles elimination.
Nirsevimab Effectiveness Against Medically Attended Respiratory Syncytial Virus Illness and Hospitalization Among Alaska Native Children — Yukon-Kuskokwim Delta Region, Alaska, October 2023–June 2024
Authors: Brian Lefferts, Sara Bressler, James W. Keck, Christine Desnoyers, Ellen Hodges, Gerald January, Kristina Morris, Leslie Herrmann, Rosalyn Singleton, Sarah Aho, Julia Rogers, Katherine Newell, Elizabeth Ohlsen, Ruth Link-Gelles, Fatimah S. Dawood, Dana Bruden, Marc Fischer, Joseph Klejka, Heather M. Scobie
Journal: MMWR Morbidity and Mortality Weekly Report (2024)

Respiratory syncytial virus (RSV) is a leading cause of hospitalization among young children. Historically, American Indian and Alaska Native (AI/AN) children have experienced high rates of RSV-associated hospitalization. In August 2023, a preventive monoclonal antibody (nirsevimab) was recommended for all infants aged <8 months (born during or entering their first RSV season) and for children aged 8-19 months (entering their second RSV season) who have increased risk for severe RSV illness, including all AI/AN children. This evaluation in Alaska's Yukon-Kuskokwim Delta region estimated nirsevimab effectiveness among AI/AN children in their first or second RSV seasons during 2023-2024. Among 472 children with medically attended acute respiratory illness (ARI), 48% overall had received nirsevimab ≥7 days earlier (median = 91 days before the ARI-related visit). For children in their first RSV season (292), nirsevimab effectiveness was 76% (95% CI = 42%-90%) against medically attended RSV illness and 89% (95% CI = 32%-98%) against RSV hospitalization. For children in their second RSV season (180), effectiveness against medically attended RSV illness was 88% (95% CI = 48%-97%). Nirsevimab is effective for preventing severe RSV illness among infants entering their first RSV season and children entering their second season with increased risk for severe RSV, including all AI/AN children.
Endometriosis: cannabidiol therapy for symptom relief
Authors: Lucy H R Whitaker, Clive Page, Charles Morgan, Andrew W Horne, Philippa T K Saunders
Journal: Trends in Pharmacological Sciences (2024)

Endometriosis is a common, chronic, incurable condition the hallmark of which is the presence of lesions (tissue resembling endometrium) in sites outside the womb, with symptoms including chronic debilitating pain and fatigue. However, current therapeutic options are limited. Recent advances in our understanding of the mechanisms that contribute to the development of lesions and pain experience in endometriosis as well as surveys of patients have increased interest in testing recently approved formulations containing cannabidiol (CBD) in this patient group. In this review, we summarise data from patient samples and animals models focussed on the pathophysiology of endometriosis, including pathways where CBD has activity. We consider the available formulations of CBD-containing products, their pharmacokinetics (PK), and their use in ongoing clinical trials in endometriosis and other pain conditions.