tbuckley/cabot-search huggingface dataset:
H3 K27M-altered glioma and diffuse intrinsic pontine glioma: Semi-systematic review of treatment landscape and future directions
Authors: Martin van den Bent, Amanda M Saratsis, Marjolein Geurts, Enrico Franceschi
Journal: Neuro-Oncology (2023)

H3 K27M-mutant diffuse glioma is a recently identified brain tumor associated with poor prognosis. As of 2016, it is classified by the World Health Organization as a distinct form of grade IV glioma. Despite recognition as an important prognostic and diagnostic feature in diffuse glioma, radiation remains the sole standard of care and no effective systemic therapies are available for H3K27M mutant tumors. This review will detail treatment interventions applied to diffuse midline glioma and diffuse intrinsic pontine glioma (DIPG) prior to the identification of the H3 K27M mutation, the current standard-of-care for H3 K27M-mutant diffuse glioma treatment, and ongoing clinical trials listed on www.clinicaltrials.gov evaluating novel therapeutics in this population. Current clinical trials were identified using clinicaltrials.gov, and studies qualifying for this analysis were active or ongoing interventional trials that evaluated a therapy in at least 1 treatment arm or cohort comprised exclusively of patients with DIPG and H3 K27M-mutant glioma. Forty-one studies met these criteria, including trials evaluating H3 K27M vaccination, chimeric antigen receptor T-cell therapy, and small molecule inhibitors. Ongoing evaluation of novel therapeutics is necessary to identify safe and effective interventions in this underserved patient population.
A micro-fragmented collagen gel as a cell-assembling platform for critical limb ischemia repair
Authors: Haeun Chung, Jung-Kyun Choi, Changgi Hong, Youngseop Lee, Ki Hyun Hong, Seung Ja Oh, Jeongmin Kim, Soo-Chang Song, Jong-Wan Kim, Sang-Heon Kim
Journal: Bioactive Materials (2023)

Critical limb ischemia (CLI) is a devastating disease characterized by the progressive blockage of blood vessels. Although the paracrine effect of growth factors in stem cell therapy made it a promising angiogenic therapy for CLI, poor cell survival in the harsh ischemic microenvironment limited its efficacy. Thus, an imperative need exists for a stem-cell delivery method that enhances cell survival. Here, a collagen microgel (CMG) cell-delivery scaffold (40 × 20 μm) was fabricated via micro-fragmentation from collagen-hyaluronic acid polyionic complex to improve transplantation efficiency. Culturing human adipose-derived stem cells (hASCs) with CMG enabled integrin receptors to interact with CMG to form injectable 3-dimensional constructs (CMG-hASCs) with a microporous microarchitecture and enhanced mass transfer. CMG-hASCs exhibited higher cell survival (p < 0.0001) and angiogenic potential in tube formation and aortic ring angiogenesis assays than cell aggregates. Injection of CMG-hASCs intramuscularly into CLI mice increased blood perfusion and limb salvage ratios by 40 % and 60 %, respectively, compared to cell aggregate-treated mice. Further immunofluorescent analysis revealed that transplanted CMG-hASCs have greater muscle regenerative and angiogenic potential, with enhanced cell survival than cell aggregates (p < 0.05). Collectively, we propose CMG as a cell-assembling platform and CMG-hASCs as promising therapeutics to treat CLI.
Periodontitis and risk of cancer: Mechanistic evidence
Authors: Giacomo Baima, Margherita Minoli, Dominique S. Michaud, Mario Aimetti, Mariano Sanz, Bruno G. Loos, Mario Romandini
Journal: Periodontology 2000 (2023)

Abstract This review aims to critically analyze the pathways of interaction and the pathogenic mechanisms linking periodontitis and oral bacteria with the initiation/progression of cancer at different body compartments. A higher risk of head and neck cancer has been consistently associated with periodontitis. This relationship has been explained by the local promotion of dysbiosis, chronic inflammation, immune evasion, and direct (epi)genetic damage to epithelial cells by periodontal pathobionts and their toxins. Epidemiological reports have also studied a possible link between periodontitis and the incidence of other malignancies at distant sites, such as lung, breast, prostate, and digestive tract cancers. Mechanistically, different pathways have been involved, including the induction of a chronic systemic inflammatory state and the spreading of oral pathobionts with carcinogenic potential. Indeed, periodontitis may promote low‐grade systemic inflammation and phenotypic changes in the mononuclear cells, leading to the release of free radicals and cytokines, as well as extracellular matrix degradation, which are all mechanisms involved in carcinogenic and metastatic processes. Moreover, the transient hematogenous spill out or micro‐aspiration/swallowing of periodontal bacteria and their virulence factors (i.e., lipopolysaccharides, fimbriae), may lead to non‐indigenous bacterial colonization of multiple microenvironments. These events may in turn replenish the tumor‐associated microbiome and thus influence the molecular hallmarks of cancer. Particularly, specific strains of oral pathobionts (e.g., Porphyromonas gingivalis and Fusobacterium nucleatum ) may translocate through the hematogenous and enteral routes, being implicated in esophageal, gastric, pancreatic, and colorectal tumorigenesis through the modulation of the gastrointestinal antitumor immune system (i.e., tumor‐infiltrating T cells) and the increased expression of pro‐inflammatory/oncogenic genes. Ultimately, the potential influence of common risk factors, relevant comorbidities, and upstream drivers, such as gerovulnerability to multiple diseases, in explaining the relationship cannot be disregarded. The evidence analyzed here emphasizes the possible relevance of periodontitis in cancer initiation/progression and stimulates future research endeavors.
Nebulised delivery of RNA formulations to the lungs: From aerosol to cytosol
Authors: Michael T. Neary, Lianne M. Mulder, Piotr S. Kowalski, Ronan MacLoughlin, Abina M. Crean, Katie B. Ryan
Journal: Journal of Controlled Release (2024)

In the past decade RNA-based therapies such as small interfering RNA (siRNA) and messenger RNA (mRNA) have emerged as new and ground-breaking therapeutic agents for the treatment and prevention of many conditions from viral infection to cancer. Most clinically approved RNA therapies are parenterally administered which impacts patient compliance and adds to healthcare costs. Pulmonary administration via inhalation is a non-invasive means to deliver RNA and offers an attractive alternative to injection. Nebulisation is a particularly appealing method due to the capacity to deliver large RNA doses during tidal breathing. In this review, we discuss the unique physiological barriers presented by the lung to efficient nebulised RNA delivery and approaches adopted to circumvent this problem. Additionally, the different types of nebulisers are evaluated from the perspective of their suitability for RNA delivery. Furthermore, we discuss recent preclinical studies involving nebulisation of RNA and analysis in in vitro and in vivo settings. Several studies have also demonstrated the importance of an effective delivery vector in RNA nebulisation therefore we assess the variety of lipid, polymeric and hybrid-based delivery systems utilised to date. We also consider the outlook for nebulised RNA medicinal products and the hurdles which must be overcome for successful clinical translation. In summary, nebulised RNA delivery has demonstrated promising potential for the treatment of several lung-related conditions such as asthma, COPD and cystic fibrosis, to which the mode of delivery is of crucial importance for clinical success.
Porous Titanium Scaffolds with Mechanoelectrical Conversion and Photothermal Function: A Win‐Win Strategy for Bone Reconstruction of Tumor‐Resected Defects
Authors: Zhen Tang, Dongmei Yu, Shusen Bao, Chenyu Li, Hao Wu, Hui Dong, Ning Wang, Yichao Liu, Qi Wu, Changcheng Chen, Mo Wang, Pengfei Cao, Zenghui Zheng, Hai Huang, Xiaokang Li, Zheng Guo
Journal: Advanced Healthcare Materials (2023)

Abstract Bone metastases severely threaten the lives of patients. Although surgical treatment combined with adjuvant chemotherapy significantly improves the survival rate of patients, tumor recurrence, or metastasis after surgical resection and bone defects caused by surgical treatment remain major challenges for clinicians. Given the abovementioned clinical requirements, barium titanate‐containing iron‐coated porous titanium alloy scaffolds have been proposed to promote bone defect repair and inhibit tumor recurrence. Fortunately, in vitro and in vivo experimental research confirms that barium titanate containing iron‐coated porous titanium alloy scaffolds promote osteogenesis and bone reconstruction in defect repair via mechanoelectric conversion and inhibit tumor recurrence via photothermal effects. Furthermore, the underlying and intricate mechanisms of bone defect repair and tumor recurrence prevention of barium titanate‐containing iron‐coated porous titanium alloy scaffolds are explored. A win‐win strategy for mechanoelectrical conversion and photothermal functionalization provides promising insights into bone reconstruction of tumor‐resected defects.
Detection and subtyping of basal cell carcinoma in whole-slide histopathology using weakly-supervised learning
Authors: Daan J. Geijs, Stephan Dooper, Witali Aswolinskiy, Lisa M. Hillen, Avital L. Amir, Geert Litjens
Journal: Medical Image Analysis (2023)

The frequency of basal cell carcinoma (BCC) cases is putting an increasing strain on dermatopathologists. BCC is the most common type of skin cancer, and its incidence is increasing rapidly worldwide. AI can play a significant role in reducing the time and effort required for BCC diagnostics and thus improve the overall efficiency of the process. To train such an AI system in a fully-supervised fashion however, would require a large amount of pixel-level annotation by already strained dermatopathologists. Therefore, in this study, our primary objective was to develop a weakly-supervised for the identification of basal cell carcinoma (BCC) and the stratification of BCC into low-risk and high-risk categories within histopathology whole-slide images (WSI). We compared Clustering-constrained Attention Multiple instance learning (CLAM) with StreamingCLAM and hypothesized that the latter would be the superior approach. A total of 5147 images were used to train and validate the models, which were subsequently tested on an internal set of 949 images and an external set of 183 images. The labels for training were automatically extracted from free-text pathology reports using a rule-based approach. All data has been made available through the COBRA dataset. The results showed that both the CLAM and StreamingCLAM models achieved high performance for the detection of BCC, with an area under the ROC curve (AUC) of 0.994 and 0.997, respectively, on the internal test set and 0.983 and 0.993 on the external dataset. Furthermore, the models performed well on risk stratification, with AUC values of 0.912 and 0.931, respectively, on the internal set, and 0.851 and 0.883 on the external set. In every single metric the StreamingCLAM model outperformed the CLAM model or is on par. The performance of both models was comparable to that of two pathologists who scored 240 BCC positive slides. Additionally, in the public test set, StreamingCLAM demonstrated a comparable AUC of 0.958, markedly superior to CLAM's 0.803. This difference was statistically significant and emphasized the strength and better adaptability of the StreamingCLAM approach.
A new clinical and prognostic characterization of the patterns of decompensation of cirrhosis
Authors: Marta Tonon, Roberta D’Ambrosio, Valeria Calvino, Giulia Tosetti, Anna Barone, Simone Incicco, Carmine Gambino, Roberta Gagliardi, Marta Borghi, Nicola Zeni, Salvatore Piano, Pietro Lampertico, Paolo Angeli
Journal: Journal of Hepatology (2023)

The prognostic impact of acute decompensation (AD), i.e. the development of complications that require hospitalization, has recently been assessed. However, complications of cirrhosis do not necessarily require hospitalization and can develop progressively, as in the recently defined non-acute decompensation (NAD). Nevertheless, there is no data regarding the incidence and prognostic impact of NAD. The aim of the study was to evaluate the incidence and the prognostic impact of NAD and AD in outpatients with cirrhosis.
Causal role of lipid metabolism in pulmonary alveolar proteinosis: an observational and mendelian randomisation study
Authors: Junfeng Huang, Zikai Lin, Jinsheng Lin, Shuojia Xie, Shixin Xia, Gengjia Chen, Ziwen Zheng, Zhe Xu, Fangcheng Liu, Hongkai Wu, Shiyue Li
Journal: Thorax (2023)

Pulmonary alveolar proteinosis (PAP) is a rare interstitial lung disease characterised by the accumulation of lipoprotein material in the alveoli. Although dyslipidaemia is a prominet feature, the causal effect of lipid traits on PAP remains unclear. This study aimed to explore the role of lipid traits in PAP and evaluate the potential of lipid-lowering drug targets in PAP. Clinical outcomes, lipid profiles and lung function tests were analysed in a clinical cohort of diagnosed PAP patients and propensity score-matched healthy controls. Genome-wide association study data on PAP, lipid metabolism, blood cells and variants of genes encoding potential lipid-lowering drug targets were obtained for Mendelian randomisation (MR) and mediation analyses. Observational results showed that higher levels of total cholesterol (TC), triglycerides and low-density lipoprotein (LDL) were associated with increased risks of PAP. Higher levels of TC and LDL were also associated with worse PAP severity. In MR analysis, elevated LDL was associated with an increased risk of PAP (OR: 4.32, 95% CI: 1.63 to 11.61, p=0.018). Elevated monocytes were associated with a lower risk of PAP (OR 0.34, 95% CI: 0.18 to 0.66, p=0.002) and mediated the risk impact of LDL on PAP. Genetic mimicry of PCSK9 inhibition was associated with a reduced risk of PAP (OR 0.03, p=0.007). Our results support the crucial role of lipid and metabolism-related traits in PAP risk, emphasising the monocyte-mediated, causal effect of elevated LDL in PAP genetics. PCSK9 mediates the development of PAP by raising LDL. These finding provide evidence for lipid-related mechanisms and promising lipid-lowering drug target for PAP.
Impact of sex on severe asthma: a cross-sectional retrospective analysis of UK primary and specialist care
Authors: Lola Loewenthal, John Busby, Ronald McDowell, Thomas Brown, Hassan Burhan, Rekha Chaudhuri, Paddy Dennison, James William Dodd, Simon Doe, Shoaib Faruqi, Robin Gore, Elfatih Idris, David Joshua Jackson, Mitesh Patel, Thomas Pantin, Ian Pavord, Paul E Pfeffer, David B Price, Hitasha Rupani, Salman Siddiqui, Liam G Heaney, Andrew Menzies-Gow
Journal: Thorax (2023)

After puberty, females are more likely to develop asthma and in a more severe form than males. The associations between asthma and sex are complex with multiple intrinsic and external factors.
Eosinophil Distribution in Eosinophilic Esophagitis and its Impact on Disease Activity and Response to Treatment
Authors: Anne Godat, Ralph Mueller, Désirée Schenker, Alain M. Schoepfer, Alex Straumann, Thomas Greuter, Philipp Schreiner, Luc Biedermann, Dagmar Simon, Hans-Uwe Simon
Journal: Clinical Gastroenterology and Hepatology (2023)
Orbital Emphysema Caused by a Tik-Tok Challenge
Authors: Erica N. Woertz, Sudarshan Srivatsan, Robert Kersten
Journal: Ophthalmology (2023)

A 21-year-old woman presented to the emergency department with 3 days of worsening periorbital swelling (A, B). She had recently completed a Tik-Tok challenge in which she induced air reflux through the nasolacrimal system by forcefully blowing against a plugged nose. Computed tomography scans (C, coronal; D, sagittal) demonstrated bilateral subcutaneous and orbital emphysema with no orbital fractures. Her swelling was managed conservatively, but she was subsequently lost to follow up. Forceful nose blowing may lead to orbital emphysema even in the absence of a visible fracture. (Magnified version of Figure A-D is available online at www.aaojournal.org).
STAT4 facilitates PD‐L1 level via IL‐12R/JAK2/STAT3 axis and predicts immunotherapy response in breast cancer
Authors: Jianbo Zhou, Feng Wan, Li Wang, Cheng Peng, Ruizhen Huang, Fu Peng
Journal: MedComm (2023)

Abstract Signal transducer and activator of transcription 4 (STAT4) is a critical transcription factor for T helper cell differentiation and tumor cells. Although its prognostic role and gene function have been reported in several carcinomas, the role of STAT4 in vitro and in vivo in breast cancer remains poorly understood. The effect of STAT4 in immunotherapy is also unclear. Therefore, we integrated bulk transcriptomics, experiments, and single‐cell transcriptomics to systematically analyze its function in prognosis and signaling pathway. Several clinical breast cancer cohorts confirmed STAT4 as a T‐cell relevant prognostic biomarker. Overexpressed STAT4 increased programmed cell death ligand 1 (PD‐L1) and major histocompatibility complex class II levels in breast cancer cells. In molecular mechanism, transcriptional synergy between STAT4 and STAT3 transactivated interleukin (IL)‐12R and involved a positive feedback loop: STAT4/IL‐12R/JAK2–STAT3–STAT4, which contributed to the upregulation of PD‐L1 expression. The above signaling axis was defined as the STAT4‐related pathway and its score was used to predict T‐cell expansion and anti‐PD1 treatment response. These findings highlight a novel molecular mechanism indirectly regulating PD‐L1 through the STAT4‐related pathway: IL‐12R/JAK2–STAT3–STAT4/PD‐L1, and it has potential application in predicting anti‐PD‐1 immunotherapy response, which may pave the way for stratified immunotherapy in breast cancer.
Long‐term immune response to Omicron‐specific mRNA vaccination in mice, hamsters, and nonhuman primates
Authors: Yi Wu, Namei Wu, Xiaoying Jia, Yan Wu, Xinghai Zhang, Yang Liu, Yuxia Hou, Yanqiong Shen, Entao Li, Wei Wang, Yucai Wang, Sandra Chiu
Journal: MedComm (2023)

Abstract Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) Omicron and its subvariants (such as BQ.1, XBB and the latest variants, including XBB.1.16, EG.5, and BA.2.86), as the dominant variants, currently account for almost all new infections in the world due to their high transmissibility and immune escape ability. Omicron‐specific mRNA vaccines showed great potential to protect against Omicron infections. However, whether the vaccine could provide long‐term protection is unknown. Toward this goal, we evaluated the immunogenicity of a preclinical Omicron (BA.1)‐specific mRNA vaccine (S Omicron ‐6P) in different animal models. S Omicron ‐6P induced the highest levels of antibody titers at 1–2 weeks in different animals after the second dose. Even 9 months after the immunization, we observed modest neutralizing activity against Omicron subvariants in macaques. In addition, immunological memory cells can be rapidly reactivated upon stimulation. S Omicron ‐6P at concentrations higher than 10 μg effectively protected hamsters from BA.1 challenge 253 days after the first immunization, which could be attributed to the reactivation of immune systems. In addition, the toxicity tests conducted in rats revealed a highly favorable biosafety profile for S Omicron ‐6P, even at high dosages. Our data suggest that the Omicron‐specific mRNA vaccine is highly effective and safe in animal models and provides long‐term immunologic protection against SARS‐CoV‐2 Omicron infections.
Cholangitis Induced by Immune Checkpoint Inhibitors: Analysis of Pharmacovigilance Data
Authors: Lucy Meunier, Lina Hountondji, Hélène Jantzem, Jean Luc Faillie, Alexandre Maria, Pascale Palassin, Stéphanie Faure, Philine Witkowski-Durand-Viel, Xavier Quantin, Georges Philippe Pageaux
Journal: Clinical Gastroenterology and Hepatology (2023)

Immune checkpoint inhibitors (ICIs) are remarkable anticancer therapies that have revolutionized the oncological prognosis of many cancers.1 The considerable efficacy of ICIs is associated with the onset of more- or less-serious, immune-related adverse effects (irAEs) affecting several organs, which can concern up to 70% of patients, owing to a loss of self-tolerance during the restoration of antitumor immunity.2 Checkpoint inhibitor-induced liver injury (CHILI), which may occur in up to 25% of patients, is treated with steroids as first-line treatment, and immunosuppressive drugs as second-line treatment.3 Recently, ICI-induced cholangitis was described as an emerging irAE. Hence, Pi et al4 reviewed all 53 published cases of ICI-induced cholangitis and compared the different types of bile duct involvement. We recently described CHILI according to the biological profile: cholestatic, hepatocellular, or mixed.5 Cholestatic profiles were associated with macroscopic and/or microscopic bile duct damage, and time to resolution was significantly longer. More recently, Onoyama et al6 and Parlati et al7 described a poorer response to steroids in cases of biliary histologic damage or ICI-induced sclerosing cholangitis. The latest European Society for Medical Oncology guidelines include the management of cholangitis, which is succinct and still poorly documented.3 The aim of this study therefore was to analyze the cases of ICI-induced cholangitis reported in the French pharmacovigilance system to describe their clinical characteristics, evolution, and outcome.
Harnessing immunotherapy for brain metastases: insights into tumor–brain microenvironment interactions and emerging treatment modalities
Authors: Dairan Zhou, Zhenyu Gong, Dejun Wu, Chao Ma, Lijun Hou, Xiaomin Niu, Tao Xu
Journal: Journal of Hematology & Oncology (2023)

Abstract Brain metastases signify a deleterious milestone in the progression of several advanced cancers, predominantly originating from lung, breast and melanoma malignancies, with a median survival timeframe nearing six months. Existing therapeutic regimens yield suboptimal outcomes; however, burgeoning insights into the tumor microenvironment, particularly the immunosuppressive milieu engendered by tumor–brain interplay, posit immunotherapy as a promising avenue for ameliorating brain metastases. In this review, we meticulously delineate the research advancements concerning the microenvironment of brain metastases, striving to elucidate the panorama of their onset and evolution. We encapsulate three emergent immunotherapeutic strategies, namely immune checkpoint inhibition, chimeric antigen receptor (CAR) T cell transplantation and glial cell-targeted immunoenhancement. We underscore the imperative of aligning immunotherapy development with in-depth understanding of the tumor microenvironment and engendering innovative delivery platforms. Moreover, the integration with established or avant-garde physical methodologies and localized applications warrants consideration in the prevailing therapeutic schema.