tbuckley/cabot-search huggingface dataset:
Unbiasedly decoding the tumor microenvironment with single-cell multiomics analysis in pancreatic cancer
Authors: Yifan Fu, Jinxin Tao, Tao Liu, Yueze Liu, Jiangdong Qiu, Dan Su, Ruobing Wang, Wenhao Luo, Zhe Cao, Guihu Weng, Taiping Zhang, Yupei Zhao
Journal: Molecular Cancer (2024)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with a poor prognosis and limited therapeutic options. Research on the tumor microenvironment (TME) of PDAC has propelled the development of immunotherapeutic and targeted therapeutic strategies with a promising future. The emergence of single-cell sequencing and mass spectrometry technologies, coupled with spatial omics, has collectively revealed the heterogeneity of the TME from a multiomics perspective, outlined the development trajectories of cell lineages, and revealed important functions of previously underrated myeloid cells and tumor stroma cells. Concurrently, these findings necessitated more refined annotations of biological functions at the cell cluster or single-cell level. Precise identification of all cell clusters is urgently needed to determine whether they have been investigated adequately and to identify target cell clusters with antitumor potential, design compatible treatment strategies, and determine treatment resistance. Here, we summarize recent research on the PDAC TME at the single-cell multiomics level, with an unbiased focus on the functions and potential classification bases of every cellular component within the TME, and look forward to the prospects of integrating single-cell multiomics data and retrospectively reusing bulk sequencing data, hoping to provide new insights into the PDAC TME.
Clinical and genomic features of Mycobacterium avium complex: a multi-national European study
Authors: Nils Wetzstein, Margo Diricks, Thomas B. Anton, Sönke Andres, Martin Kuhns, Thomas A. Kohl, Carsten Schwarz, Astrid Lewin, Jan Kehrmann, Barbara C. Kahl, Annika Schmidt, Stefan Zimmermann, Moritz K. Jansson, Sophie A. Baron, Bettina Schulthess, Michael Hogardt, Inna Friesen, Stefan Niemann, Thomas A. Wichelhaus
Journal: Genome Medicine (2024)

The Mycobacterium avium complex (MAC) comprises the most frequent non-tuberculous mycobacteria (NTM) in Central Europe and currently includes twelve species. M. avium (MAV), M. intracellulare subsp. intracellulare (MINT), and M. intracellulare subsp. chimaera (MCH) are clinically most relevant. However, the population structure and genomic landscape of MAC linked with potential pathobiological differences remain little investigated.
L-Wnk1 Deletion in Smooth Muscle Cells Causes Aortitis and Inflammatory Shift
Authors: Helene Quelquejay, Rida Al-Rifai, Michele Silvestro, Marie Vandestienne, Irmine Ferreira, Tristan Mirault, Daniel Henrion, Xiaodan Zhong, Icia Santos-Zas, Guillaume Goudot, Paul Alayrac, Estelle Robidel, Gwennhael Autret, Daniel Balvay, Soraya Taleb, Alain Tedgui, Chantal M. Boulanger, Alma Zernecke, Antoine-Emmanuel Saliba, Juliette Hadchouel, Bhama Ramkhelawon, Clement Cochain, Sonia Bergaya, Xavier Jeunemaitre, Hafid Ait-Oufella
Journal: Circulation Research (2024)

BACKGROUND: The long isoform of the Wnk1 (with-no-lysine [K] kinase 1) is a ubiquitous serine/threonine kinase, but its role in vascular smooth muscle cells (VSMCs) pathophysiology remains unknown. METHODS: AngII (angiotensin II) was infused in Apoe −/− to induce experimental aortic aneurysm. Mice carrying an Sm22-Cre allele were cross-bred with mice carrying a floxed Wnk1 allele to specifically investigate the functional role of Wnk1 in VSMCs. RESULTS: Single-cell RNA-sequencing of the aneurysmal abdominal aorta from AngII-infused Apoe −/− mice revealed that VSMCs that did not express Wnk1 showed lower expression of contractile phenotype markers and increased inflammatory activity. Interestingly, WNK1 gene expression in VSMCs was decreased in human abdominal aortic aneurysm. Wnk1 -deficient VSMCs lost their contractile function and exhibited a proinflammatory phenotype, characterized by the production of matrix metalloproteases, as well as cytokines and chemokines, which contributed to local accumulation of inflammatory macrophages, Ly6C hi monocytes, and γδ T cells. Sm22Cre+Wnk1 lox/lox mice spontaneously developed aortitis in the infrarenal abdominal aorta, which extended to the thoracic area over time without any negative effect on long-term survival. AngII infusion in Sm22Cre+Wnk1 lox/lox mice aggravated the aortic disease, with the formation of lethal abdominal aortic aneurysms. Pharmacological blockade of γδ T-cell recruitment using neutralizing anti-CXCL9 (anti-CXC motif chemokine ligand 9) antibody treatment, or of monocyte/macrophage using Ki20227, a selective inhibitor of CSF1 receptor, attenuated aortitis. Wnk1 deletion in VSMCs led to aortic wall remodeling with destruction of elastin layers, increased collagen content, and enhanced local TGF-β (transforming growth factor-beta) 1 expression. Finally, in vivo TGF-β blockade using neutralizing anti-TGF-β antibody promoted saccular aneurysm formation and aorta rupture in Sm22 Cre+ Wnk1 lox/lox mice but not in control animals. CONCLUSION: Wnk1 is a key regulator of VSMC function. Wnk1 deletion promotes VSMC phenotype switch toward a pathogenic proinflammatory phenotype, orchestrating deleterious vascular remodeling and spontaneous severe aortitis in mice.
Clinical significance of circulating tumor cells in colorectal cancer with peritoneal metastases: a prospective cohort study using a novel method for monitoring treatment response, and assessing minimal residual disease
Authors: Petter Frühling, Louice Moberg, Lana Ghanipour, Helgi Birgisson, Wilhelm Graf, Christer Ericsson, P.H. Cashin
Journal: International Journal of Surgery (2024)
The roles of tertiary lymphoid structures in genitourinary cancers: molecular mechanisms, therapeutic strategies, and clinical applications
Authors: Jie Yang, Xingyu Xiong, Weitao Zheng, Hang Xu, Xinyang Liao, Qiang Wei, Lu Yang
Journal: International Journal of Surgery (2024)

The presence of tertiary lymphoid structures (TLSs) associated with distinct treatment efficacy and clinical prognosis has been identified in various cancer types. However, the mechanistic roles and clinical implications of TLSs in genitourinary (GU) cancers remain incompletely explored. Despite their potential role as predictive markers described in numerous studies, it is essential to comprehensively evaluate the characteristics of TLSs, including drivers of formation, structural foundation, cellular compositions, maturation stages, molecular features, and specific functionality to maximize their positive impacts on tumor-specific immunity. The unique contributions of these structures to cancer progression and biology have fueled interest in these structures as mediators of antitumor immunity. Emerging data are trying to explore the effects of therapeutic interventions targeting TLSs. Therefore, a better understanding of the molecular and phenotypic heterogeneity of TLSs may facilitate the development of TLSs-targeting therapeutic strategies to obtain optimal clinical benefits for GU cancers in the setting of immunotherapy. In this review, the authors focus on the phenotypic and functional heterogeneity of TLSs in cancer progression, current therapeutic interventions targeting TLSs and the clinical implications and therapeutic potential of TLSs in GU cancers.
Nonsense CD247 mutations show dominant-negative features in T-cell receptor expression and function
Authors: Alejandro C. Briones, Rebeca F. Megino, Ana V. Marin, Daniel Chacón-Arguedas, Elena García-Martinez, Héctor Balastegui-Martín, Hugh T. Reyburn, Sarah E. Henrickson, Carmen Rodríguez-Sainz, Elena Seoane-Reula, Paloma Sanchez-Mateos, Paula P. Cardenas, Jose R. Regueiro
Journal: Journal of Allergy and Clinical Immunology (2024)

The invariant TCR ζ/CD247 homodimer is crucial for TCR/CD3 expression and signaling through its 3 immunoreceptor tyrosine-based activation motifs (ITAMs). Homozygous null mutations in CD247 lead to immunodeficiency, while carriers exhibit 50% reduced surface CD3. It is unclear whether carriers of other CD247 variants show dominant-negative effects.
Bioengineered Abiotic Nanomaterials Through Cell Membrane‐Camouflaging: Advancements and Challenges in Lung Cancer
Authors: Xuru Jin, Daniela Lopes, Joana Lopes, Zhidan Hua, Ying Lei, Roham Ghanbari, Ehsan Nazarzadeh Zare, Assunta Borzacchiello, Hassan Karimi Male, Siavash Iravani, Mika Sillanpää, Chander Prakash, Xiangdong Wang, Ana Cláudia Paiva‐Santos, Pooyan Makvandi, Yi Xu
Journal: Advanced Healthcare Materials (2024)

Lung cancer remains a major global health concern with high mortality rates and poor prognosis. Bridging the gap between the chemical and cellular understanding of cell-decorated biomimetic nanocomposites and their clinical translation is crucial for developing effective therapies. Nanocomposites show promise in targeted drug delivery and diagnostics, but their clinical application is hindered by biocompatibility and clearance issues. To overcome these challenges, biomimetic approaches utilizing cell membrane-coated nanomaterials emerge. By camouflaging nanomaterials with cell membranes, the biointerfaces are enhanced, and the inherent properties of the donor cell membranes are acquired. This review provides an overview of recent advancements on cell membrane-coated nanocomposites for lung cancer diagnosis and treatment. It discusses fabrication techniques, biomedical applications, challenges, and future prospects. The incorporation of cell membranes into nanocomposites holds potential for improved lung cancer therapy, but further development and refinement are needed for precise tumor targeting. Addressing the identified challenges will pave the way for clinical translation of these biomimetic nanoplatforms and advance lung cancer diagnosis and treatment.
Redox‐Responsive Hydrogels Loaded with an Antibacterial Peptide as Controlled Drug Delivery for Healing Infectious Wounds
Authors: Mariam Cherri, Paraskevi S. Stergiou, Zainab Ahmadian, Tatyana L. Povolotsky, Boonya Thongrom, Xin Fan, Ehsan Mohammadifar, Rainer Haag
Journal: Advanced Healthcare Materials (2024)

Abstract Infectious wounds occur when harmful microorganisms such as bacteria or viruses invade a wound site. Its problems associated include delayed healing, increased pain, swelling, and the potential for systemic infections. Therefore, developing new wound dressing materials with antibacterial effects is crucial for improving the healing process. Here a redox‐degradable hydrogel loaded with an antibacterial peptide (vancomycin) in a straightforward gram‐scale synthesis, is developed. The hydrogel structure consists of a disulfide bond‐containing hyperbranched polyglycerol (SS‐hPG) that is cross‐linked by 4‐arm polyethylene glycol‐thiol (4‐arm PEG‐SH). The polymerization mechanism and full characterization of SS‐hPG are described as this synthesis is reported for the first time. Rheology is used to ascertain the hydrogel's mechanical characteristics, such as stiffness, and self‐healing, determining these properties for different ratios and concentrations of both gel components. The incorporation of disulfide bonds in the hydrogel is proved by conducting degradation experiments in reductive environments. Fluorescein isothiocyanate‐albumin (FITC‐BSA) and vancomycin both are loaded into the gel, and the guest release kinetics is assessed for both slow and on‐demand releases. Finally, the in vitro and in vivo experiments prove that the vancomycin‐loaded hydrogel acts as an antibacterial barrier for wound dressing and accelerates the healing of infectious wounds in a mouse model.
A 3D Pancreatic Cancer Model with Integrated Optical Sensors for Noninvasive Metabolism Monitoring and Drug Screening
Authors: Anna Chiara Siciliano, Stefania Forciniti, Valentina Onesto, Helena Iuele, Donatella Delle Cave, Federica Carnevali, Giuseppe Gigli, Enza Lonardo, Loretta L. del Mercato
Journal: Advanced Healthcare Materials (2024)

A distinct feature of pancreatic ductal adenocarcinoma (PDAC) is a prominent tumor microenvironment (TME) with remarkable cellular and spatial heterogeneity that meaningfully impacts disease biology and treatment resistance. The dynamic crosstalk between cancer cells and the dense stromal compartment leads to spatially and temporally heterogeneous metabolic alterations, such as acidic pH that contributes to drug resistance in PDAC. Thus, monitoring the extracellular pH metabolic fluctuations within the TME is crucial to predict and to quantify anticancer drug efficacy. Here, a simple and reliable alginate-based 3D PDAC model embedding ratiometric optical pH sensors and cocultures of tumor (AsPC-1) and stromal cells for simultaneously monitoring metabolic pH variations and quantify drug response is presented. By means of time-lapse confocal laser scanning microscopy (CLSM) coupled with a fully automated computational analysis, the extracellular pH metabolic variations are monitored and quantified over time during drug testing with gemcitabine, folfirinox, and paclitaxel, commonly used in PDAC therapy. In particular, the extracellular acidification is more pronounced after drugs treatment, resulting in increased antitumor effect correlated with apoptotic cell death. These findings highlight the importance of studying the influence of cellular metabolic mechanisms on tumor response to therapy in 3D tumor models, this being crucial for the development of personalized medicine approaches.
Root surface biomodification in periodontal therapy: Biological rationale and clinical applications
Authors: Muhammad H. A. Saleh, Debora R. Dias, Andrea Ravida, Hom‐Lay Wang
Journal: Periodontology 2000 (2024)

Abstract Regenerative periodontal therapy aims to form new cementum, periodontal ligament, and alveolar bone, all sealed by gingival tissue. The root surface acts as the wound margin during this regeneration process. Root surface biomodification (root conditioning/root decontamination), therefore, seems instrumental in promoting surface decontamination and enhancing tissue attachment by removing the smear layer, exposing collagen fibrils, and facilitating blood clot formation and stabilization. This review attempted to provide an all‐encompassing, evidence‐based assessment of the role of root surface biomodification in regenerative periodontal therapy, particularly in intrabony defects, furcation defects, and root coverage procedures. The reviewed evidence suggested that root conditioning agents, whether used independently or in conjunction with bone graft materials, biological agents, membranes, or connective tissue grafts, do not offer any clinical advantage regarding clinical attachment gain. Thus, integrating chemical methods with the mechanical root instrumentation process does not necessarily contribute to superior clinical outcomes.
2023 American College of Rheumatology (ACR)/American College of Chest Physicians (CHEST) Guideline for the Treatment of Interstitial Lung Disease in People with Systemic Autoimmune Rheumatic Diseases
Authors: Sindhu R. Johnson, Elana J. Bernstein, Marcy B. Bolster, Jonathan H. Chung, Sonye K. Danoff, Michael D. George, Dinesh Khanna, Gordon Guyatt, Reza D. Mirza, Rohit Aggarwal, Aberdeen Allen, Shervin Assassi, Lenore Buckley, Hassan A. Chami, Douglas S. Corwin, Paul F. Dellaripa, Robyn T. Domsic, Tracy J. Doyle, Catherine Marie Falardeau, Tracy M. Frech, Fiona K. Gibbons, Monique Hinchcliff, Cheilonda Johnson, Jeffrey P. Kanne, John S. Kim, Sian Yik Lim, Scott Matson, Zsuzsanna H. McMahan, Samantha J. Merck, Kiana Nesbitt, Mary Beth Scholand, Lee Shapiro, Christine D. Sharkey, Ross Summer, John Varga, Anil Warrier, Sandeep K. Agarwal, Danielle Antin‐Ozerkis, Bradford Bemiss, Vaidehi Chowdhary, Jane E. Dematte D'Amico, Robert Hallowell, Alicia M. Hinze, Patil A. Injean, Nikhil Jiwrajka, Elena K. Joerns, Joyce S. Lee, Ashima Makol, Gregory C. McDermott, Jake G. Natalini, Justin M. Oldham, Didem Saygin, Kimberly Showalter Lakin, Namrata Singh, Joshua J. Solomon, Jeffrey A. Sparks, Marat Turgunbaev, Samera Vaseer, Amy Turner, Stacey Uhl, Ilya Ivlev
Journal: Arthritis & Rheumatology (2024)

We provide evidence-based recommendations regarding the treatment of interstitial lung disease (ILD) in adults with systemic autoimmune rheumatic diseases (SARDs).
Risk factors for cement leakage after percutaneous vertebral augmentation for osteoporotic vertebral compression fractures: a meta-analysis
Authors: Yu Wu, Zelin Zhou, Guoliang Lu, Linqiang Ye, Aotian Lao, Shuai Ouyang, Zefeng Song, Zhigang Zhang
Journal: International Journal of Surgery (2024)

Background: Osteoporotic vertebral compression fractures (OVCF) may necessitate percutaneous vertebral augmentation (PVA), a procedure not without its risks. One notable complication is cement leakage (CL), which can cause significant distress in patients. Despite its clinical importance, there remains a paucity of meta-analyses investigating these complications and their management in the existing literature. Material and Methods: We systematically reviewed PubMed, Cochrane Library, Embase, and Web of Science databases up to February 2024 to identify studies examining CL following PVA treatment in OVCF. We assessed the quality of eligible cohort studies using the Newcastle-Ottawa Scale (NOS), extracted data on incidence, identified risk factors for CL, and conducting meta-analysis with Revman 5.2 software. We calculated odd ratios (OR) and Mean Differences (MD) with 95% confidence interval (CI) applying random effects models. Results: We identified twelve cohort studies that matched our strict inclusion criteria. These studies included a total of 2388 patients and 3392 vertebrae. CL was identified in 1132 vertebrae. Notable risk factors for CL included compromised cortical bone integrity (OR 5.00, 95% CI 3.01~8.29, P &lt;0.00001), presence of intravertebral vacuum clefts (OR 1.68, 95% CI 1.07~2.65, P =0.03), basivertebral foramen sign (OR 1.77, 95% CI 1.09~2.89, P =0.02), and volume of cement used (MD 0.75, 95% CI 0.41~1.10, P &lt;0.0001). Conclusion: Our findings underscore the significance of cortical bone integrity, intravertebral vacuum cleft, basivertebral foramen sign, and cement volume as principal determinants of CL risk in PVA for OVCF. These insights advocate for tailored surgical strategies to mitigate the risk of CL in this patient population.
Recombinant H77C gpE1/gpE2 heterodimer elicits superior HCV cross-neutralisation than H77C gpE2 alone
Authors: Juthika Kundu, Hoa T. Le, Michael Logan, Darren Hockman, Abdolamir Landi, Kevin Crawford, Mark Wininger, Janelle Johnson, Joydeb K. Kundu, E. Alana Tiffney, Richard A. Urbanowicz, Jonathan K. Ball, Justin R. Bailey, Jens Bukh, Mansun Law, Steven Foung, D. Lorne Tyrrell, Michael Houghton, John Lokman Law
Journal: Journal of Hepatology (2024)

Background & AimsAn optimal HCV vaccine requires the induction of antibodies that neutralise the infectivity of many heterogenous viral isolates. In this study, we have focused on determining the optimal recombinant envelope glycoprotein component to elicit cross-neutralising antibodies against global HCV genotypes. We compared the immunoreactivity and antigenicity of the recombinant HCV genotype 1a strain H77C envelope glycoprotein heterodimer gpE1/gpE2 with that of recombinant gpE2 alone derived from an infectious molecular clone (H77C).MethodsCharacterization of the envelope glycoproteins was accomplished by determining their ability to bind to a panel of broadly cross-neutralising monoclonal antibodies (bNAbs). Immunogenicity was determined by testing the ability of vaccine antisera to neutralise the infectivity in vitro of a panel of pseudotyped HCV particles in which gpE1/gpE2 derived from representative isolates of the major global HCV genotypes were displayed.ResultsgpE1/gpE2 binds to more diverse bNabs than gpE2 alone and elicits a broader profile of cross-neutralising antibodies in animals, especially against more heterologous, non-1a genotypes. While not all heterologous HCV strains can be potently inhibited in vitro by gpE1/gpE2 antisera derived from a single HCV strain, the breadth of heterologous cross-neutralisation is shown to be substantial.ConclusionsOur work supports the inclusion of gpE1/gpE2 in an HCV vaccine in order to maximise the cross-neutralisation of heterogenous HCV isolates. Our data also offers future directions in formulating a cocktail of gpE1/gpE2 antigens from a small selection of HCV genotypes to further enhance cross-neutralisation of global HCV strains and hopefully, achieving global protection.Impact and implicationsAn HCV vaccine is urgently required to prevent the high global incidence of HCV infection and disease. Since HCV is a highly heterogeneous virus, it is desirable for a vaccine to elicit antibodies that neutralise the infectivity of most global strains. To this end, we have compared the immunoreactivity and antigenicity of recombinant H77C E1E2 heterodimer with that of H77C E2 alone and show that the former exhibits more cross-neutralising epitopes and demonstrates a broader cross-neutralisation profile in vitro. In addition, our data suggests a way to further broaden cross-neutralisation using a combination of E1E2 antigens derived from a few different HCV clades. Our work provides encouragement for the development of an effective global HCV vaccine.
Corneal Opacity in the United States: An American Academy of Ophthalmology IRIS® Registry (Intelligent Research in Sight) Study
Authors: Rohan Bir Singh, Thomas H. Dohlman, Alexander Ivanov, Nathan Hall, Connor Ross, Tobias Elze, Joan W. Miller, Alice Lorch, Erdem Yuksel, Jia Yin, Reza Dana
Journal: Ophthalmology (2024)
TB PCR in BAL and EBUS-TBNA samples for the diagnosis of pulmonary and mediastinal lymph node TB: retrospective TRiBE study
Authors: Mirae Park, Kartik Kumar, Meg Coleman, Laura Martin, Georgina Russell, Pauline Scheelbeek, Ajit Lalvani, Giovanni Satta, Onn Min Kon
Journal: Thorax (2024)

Introduction The role of Xpert Ultra in bronchoalveolar lavage (BAL) and endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) samples for pulmonary and mediastinal lymph node tuberculosis (TB) remains unclear. Methods This was a retrospective observational service evaluation at a tertiary TB centre in a low-incidence setting. The diagnostic indices of Xpert Ultra, smear and culture (with cytology for EBUS-TBNA samples) were compared with culture positivity or a composite reference standard of clinical TB diagnosis. Trace readouts, a new category of results for Xpert Ultra indicating low bacillary load, were analysed in two ways as a true positive or true negative result. 282 BAL and 139 EBUS-TBNA samples were included in the analysis. Results BAL: sensitivity with 95% CI against culture-confirmed pulmonary TB from BAL samples for Xpert Ultra (trace as positive) was 0.91 (0.82 to 0.98), Xpert Ultra (trace as negative) was 0.76 (0.69 to 0.83), smear was 0.38 (p=0.0009) and culture was 1.00 (0.91 to 1.00). Specificities for all the tests were ≥0.99 (0.98 to 1.00). The addition of smear to Xpert Ultra did not improve the diagnostic accuracy. EBUS-TBNA: sensitivity against culture-confirmed TB from EBUS-TBNA samples for Xpert Ultra (trace as positive) was 0.71 (0.63 to 0.78), Xpert Ultra (trace as negative) was 0.59 (0.54 to 0.63), smear was 0.12 (p=0.002), culture was 1.00 (0.89 to 1.00), cytology was 0.87 (0.76 to 0.98) and rapid on-site evaluation of cytology (ROSE) was 0.92 (0.78 to 1.00). Specificities were 0.99 (0.97 to 1.00), 0.99 (0.97 to 1.00), 1.00 (0.98 to 1.00), 1.00 (0.98 to 1.00), 0.67 (0.67 to 0.68) and 0.42, respectively. Conclusion Xpert Ultra had a significantly higher sensitivity compared with smear in both BAL and EBUS-TBNA samples. Xpert Ultra had a lower sensitivity compared with culture but comparable specificity with results being available within &lt;24 hours. Trace readings in our low-incidence setting were associated with culture positivity in all BAL samples.