tbuckley/cabot-search huggingface dataset:
Natural lung-tropic T<sub>H</sub>9 cells: a sharp weapon for established lung metastases
Authors: Tao Chen, Chenxiao Qiao, Eloy Yinwang, Shengdong Wang, Xuehuan Wen, Yixuan Feng, Xiangang Jin, Shuming Li, Yucheng Xue, Hao Zhou, Wenkan Zhang, Xianchang Zeng, Zenan Wang, Hangxiang Sun, Lifeng Jiang, Hengyuan Li, Binghao Li, Zhijian Cai, Zhaoming Ye, Nong Lin
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background Lung metastasis remains the primary cause of tumor-related mortality, with limited treatment options and unsatisfactory efficacy. In preclinical studies, T helper 9 (T H 9) cells have shown promise in treating solid tumors. However, it is unclear whether T H 9 cells can tackle more challenging situations, such as established lung metastases. Moreover, comprehensive exploration into the nuanced biological attributes of T H 9 cells is imperative to further unravel their therapeutic potential. Methods We adoptively transferred T H 1, T H 9, and T H 17 cells into subcutaneous, in situ , and established lung metastases models of osteosarcoma and triple-negative breast cancer, respectively, comparing their therapeutic efficacy within each distinct model. We employed flow cytometry and an in vivo imaging system to evaluate the accumulation patterns of T H 1, T H 9, and T H 17 cells in the lungs after transfusion. We conducted bulk RNA sequencing on in vitro differentiated T H 9 cells to elucidate the chemokine receptor CXCR4, which governs their heightened pulmonary tropism relative to T H 1 and T H 17 cell counterparts. Using Cd4 cre Cxcr4 flox/flox mice, we investigate the effects of CXCR4 on the lung tropism of T H 9 cells. We performed mass spectrometry to identify the E3 ligase responsible for CXCR4 ubiquitination and elucidated the mechanism governing CXCR4 expression within T H 9 cellular milieu. Ultimately, we analyzed the tumor immune composition after T H 9 cell transfusion and evaluated the therapeutic efficacy of adjunctive anti-programmed cell death protein-1 (PD-1) therapy in conjunction with T H 9 cells. Results In this study, we provide evidence that T H 9 cells exhibit higher lung tropism than T H 1 and T H 17 cells, thereby exhibiting exceptional efficacy in combating established lung metastases. CXCR4-CXCL12 axis is responsible for lung tropism of T H 9 cells as ablating CXCR4 in CD4 + T cells reverses their lung accumulation. Mechanistically, tumor necrosis factor receptor-associated factor 6 (TRAF6)-driven hyperactivation of NF-κB signaling in T H 9 cells inhibited ITCH-mediated ubiquitination of CXCR4, resulting in increased CXCR4 accumulation and enhanced lung tropism of T H 9 cells. Besides, T H 9 cells’ transfusion significantly improved the immunosuppressed microenvironment. T H 9 cells and anti-PD-1 exhibit synergistic effects in tumor control. Conclusions Our findings emphasized the innate lung tropism of T H 9 cells driven by the activation of TRAF6, which supports the potential of T H 9 cells as a promising therapy for established lung metastases.
Durable antitumor response via an oncolytic virus encoding decoy-resistant IL-18
Authors: Yan Cheng, Yuanhui Zhao, Yu Liu, Yichi Zhang, Dongge Xu, Weikang Sun, Mengyu Zhang, Yuqing Miao, Susu He, Yayi Hou, Dwayne Stupack, Erguang Li
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background Interleukin-18 (IL-18), or interferon (IFN)-γ-inducing factor, potentiates T helper 1 and natural killer cell activation as well as CD8 + T-cell proliferation. Recombinant IL-18 has displayed limited clinical efficacy in part due to the expression of the decoy receptor, IL-18 binding protein (IL-18BP). A series of IL-18 variants that are devoid of IL-18BP binding, termed DR18 (decoy-resistant IL-18), was developed via directed evolution. We tested DR18 using oncolytic adenovirus (oAd) as a platform for delivery in syngeneic mouse tumor models. Methods oAd harboring wild-type IL-18 or DR18 (oAdDR18) was constructed by inserting IL-18 mutant into modified oAd backbone with Ad5/3 chimeric fiber. The delivery effect and IFN-γ induction were determined by ELISA. The antitumor efficiency of oAdDR18 was tested in CT26, B16BL6 and 4T1 tumor-bearing mice, or athymic nude mice and compared with recombinant DR18 protein (rDR18). 4T1 lung metastasis model was used to evaluate the antitumor efficiency of local and distant tumors. Antitumor memory and synergistic effect with an anti-programmed cell death protein-1 (PD-1) antibody was evaluated. The phenotypes of the immune cells in tumor microenvironment were analyzed by flow cytometry and immunohistochemistry. Results Mice received oAdDR18 maintained stable production of IL-18 and IFN-γ compared with those received rDR18. Intratumoral delivery of oAdDR18 significantly reduced tumor growth across several tumor models, but not in the athymic nude mouse model. Mice that had tumor remission showed antitumor memory. The antitumor effect was associated with intratumor infiltration of CD4 + and CD8 + T cells. DR18 delivered by oAd demonstrated long-lasting and enhanced antitumor activities against local and distant tumors compared with that received rDR18 or wild-type IL-18 delivered by oAd (oAdwtIL-18). oAdDR18 treatment also reduced 4T1 lung metastasis. In addition, combination of this virotherapy with immune checkpoint inhibitors (ICIs) like the anti-PD-1 antibody further enhanced the antitumor activity as compared with respective monotherapy. Conclusions oAdDR18 demonstrates enhanced antitumor activities through the induction of stronger local and system immunities and modulation of the tumor microenvironment compared with those of oAdwtIL-18 and rDR18. A combination of oncolytic virotherapy with cytokine engineering would lead to cytokine-based therapeutics for cancer and other diseases.
Fabrication of a transforming growth factor β1 functionalized silk sericin hydrogel through genetical engineering to repair alveolar bone defects in rabbit
Authors: Feng Wang, Anfeng Ning, Xuecheng Sun, Yujuan Zhou, Hanxin Deng, Hongji Zhou, Siyu Chen, Mengyao He, Zihan Meng, Yushu Wang, Hongfei Xia, Xu Ma, Qingyou Xia
Journal: Biomaterials (2024)
Use of artificial intelligence chatbots in clinical management of immune-related adverse events
Authors: Zixiang Zhou, Hanping Wang
Journal: Journal for ImmunoTherapy of Cancer (2024)

Artificial intelligence (AI) is progressing rapidly, with various new technologies emerging. Among these, AI chatbots have attracted considerable attention in both AI and medical fields. Concerns regarding their predictive use, accuracy, safety, and social acceptance in treatment remain pertinent.
Mitochondrial metabolic reprogramming of macrophages and T cells enhances CD47 antibody-engineered oncolytic virus antitumor immunity
Authors: Jing Zhao, Shichuan Hu, Zhongbing Qi, Xianglin Xu, Xiangyu Long, Anliang Huang, Jiyan Liu, Ping Cheng
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background Although immunotherapy can reinvigorate immune cells to clear tumors, the response rates are poor in some patients. Here, CD47 antibody-engineered oncolytic viruses (oAd-αCD47) were employed to lyse tumors and activate immunity. The oAd-αCD47 induced comprehensive remodeling of the tumor microenvironment (TME). However, whether the acidic TME affects the antitumor immunotherapeutic effects of oncolytic viruses-αCD47 has not been clarified. Methods To assess the impact of oAd-αCD47 treatment on the TME, we employed multicolor flow cytometry. Glucose uptake was quantified using 2NBDG, while mitochondrial content was evaluated with MitoTracker FM dye. pH imaging of tumors was performed using the pH-sensitive fluorophore SNARF-4F. Moreover, changes in the calmodulin-dependent protein kinase II (CaMKII)/cyclic AMP activates-responsive element-binding proteins (CREB) and peroxisome proliferator-activated receptor gamma coactivator-1α (PGC1α) signaling pathway were confirmed through western blotting and flow cytometry. Results Here, we identified sodium bicarbonate (NaBi) as the potent metabolic reprogramming agent that enhanced antitumor responses in the acidic TME. The combination of NaBi and oAd-αCD47 therapy significantly inhibited tumor growth and produced complete immune control in various tumor-bearing mouse models. Mechanistically, combination therapy mainly reduced the number of regulatory T cells and enriched the ratio of M1-type macrophages TAMs (M1.TAMs) to M2-type macrophages TAMs (M2.TAMs), while decreasing the abundance of PD-1 + TIM3 + expression and increasing the expression of CD107a in the CD8 + T cells. Furthermore, the combination therapy enhanced the metabolic function of T cells and macrophages by upregulating PGC1α, a key regulator of mitochondrial biogenesis. This metabolic improvement contributed to a robust antitumor response. Notably, the combination therapy also promoted the generation of memory T cells, suggesting its potential as an effective neoadjuvant treatment for preventing postoperative tumor recurrence and metastasis. Conclusions Tumor acidic microenvironment impairs mitochondrial energy metabolism in macrophages and T cells inducing oAd-αCD47 immunotherapeutic resistance. NaBi improves the acidity of the TME and activates the CaMKII/CREB/PGC1α mitochondrial biosynthesis signaling pathway, which reprograms the energy metabolism of macrophages and T cells in the TME, and oral NaBi enhances the antitumor effect of oAd-αCD47.
SiRCle (Signature Regulatory Clustering) model integration reveals mechanisms of phenotype regulation in renal cancer
Authors: Ariane Mora, Christina Schmidt, Brad Balderson, Christian Frezza, Mikael Bodén
Journal: Genome Medicine (2024)

Abstract Background Clear cell renal cell carcinoma (ccRCC) tumours develop and progress via complex remodelling of the kidney epigenome, transcriptome, proteome and metabolome. Given the subsequent tumour and inter-patient heterogeneity, drug-based treatments report limited success, calling for multi-omics studies to extract regulatory relationships, and ultimately, to develop targeted therapies. Yet, methods for multi-omics integration to reveal mechanisms of phenotype regulation are lacking. Methods Here, we present SiRCle ( Si gnature R egulatory Cl ust e ring), a method to integrate DNA methylation, RNA-seq and proteomics data at the gene level by following central dogma of biology, i.e. genetic information proceeds from DNA, to RNA, to protein. To identify regulatory clusters across the different omics layers, we group genes based on the layer where the gene’s dysregulation first occurred. We combine the SiRCle clusters with a variational autoencoder (VAE) to reveal key features from omics’ data for each SiRCle cluster and compare patient subpopulations in a ccRCC and a PanCan cohort. Results Applying SiRCle to a ccRCC cohort, we showed that glycolysis is upregulated by DNA hypomethylation, whilst mitochondrial enzymes and respiratory chain complexes are translationally suppressed. Additionally, we identify metabolic enzymes associated with survival along with the possible molecular driver behind the gene’s perturbations. By using the VAE to integrate omics’ data followed by statistical comparisons between tumour stages on the integrated space, we found a stage-dependent downregulation of proximal renal tubule genes, hinting at a loss of cellular identity in cancer cells. We also identified the regulatory layers responsible for their suppression. Lastly, we applied SiRCle to a PanCan cohort and found common signatures across ccRCC and PanCan in addition to the regulatory layer that defines tissue identity. Conclusions Our results highlight SiRCle’s ability to reveal mechanisms of phenotype regulation in cancer, both specifically in ccRCC and broadly in a PanCan context. SiRCle ranks genes according to biological features. https://github.com/ArianeMora/SiRCle_multiomics_integration .
Endoscopic removal of a challenging gastric foreign body causing unexplained abdominal pain
Authors: Huijie Wu, Xiaolu Lin, Wanyin Deng
Journal: Endoscopy (2024)

A 33-year-old woman presented with a 3-month history of upper abdominal pain, which was exacerbated by bending or twisting. Blood tests revealed no abnormalities, and pharmacological interventions failed to alleviate symptoms. Gastroscopy at a local hospital had shown a 0.6-cm firm protrusion on the greater curvature of the gastric antrum, without discoloration or texture changes, that was suspicious for a submucosal tumor (SMT) ([Fig. 1] a). However, gastroscopy at our center revealed that the lesion had shrunk in size compared to the initial assessment, casting doubt on the SMT diagnosis ([Fig. 1] b). Subsequent endoscopic ultrasound (EUS) showed a cordlike hyperechoic shadow penetrating the gastric muscular layer, suggesting the presence of a foreign body ([Fig. 1] c). Despite the patient denying ingestion of any foreign object, a computed tomography scan corroborated the EUS findings ([Fig. 1] d). Given the patient's persistent pain and the shrinkage of the lesion, endoscopic submucosal dissection (ESD) was carried out with her consent ([Video 1]). After the lesion had been marked and a circular incision had been made, intraoperative EUS helped to locate the deeply embedded foreign body ([Fig. 2] a–c). The foreign body was carefully extracted and found to be a sharp, 2-cm metallic object (iron wire), which had caused the gastric mucosal lesion to resemble an SMT ([Fig. 2] d,e). The wound was closed with endoscopic clips, and no bleeding was observed ([Fig. 2] f). The patient was discharged 5 days after the operation, with no recurrence of pain reported at the 2-month follow-up.
Apolipoprotein E aggregation in microglia initiates Alzheimer’s disease pathology by seeding β-amyloidosis
Authors: Seiji Kaji, Stefan A. Berghoff, Lena Spieth, Lennart Schlaphoff, Andrew O. Sasmita, Simona Vitale, Luca Büschgens, Shreeya Kedia, Martin Zirngibl, Taisiia Nazarenko, Alkmini Damkou, Leon Hosang, Constanze Depp, Frits Kamp, Patricia Scholz, David Ewers, Martin Giera, Till Ischebeck, Wolfgang Wurst, Benedikt Wefers, Martina Schifferer, Michael Willem, Klaus-Armin Nave, Christian Haass, Thomas Arzberger, Sarah Jäkel, Oliver Wirths, Gesine Saher, Mikael Simons
Journal: Immunity (2024)
Nobel Prizes honour AI pioneers and pioneering AI
Authors: Talha Burki
Journal: The Lancet Digital Health (2024)

Protein structure is not trivial. The shape determines the function—whether the protein becomes haemoglobin, hair, hormone, or horn. One way to figure out the shape of a given protein is guesswork: you could try every possible combination that the chain of amino acids could twist and fold itself into. The downside to this approach is that it takes longer than the age of the universe. An experimental approach is a better bet. It typically takes around a year, with some luck, a lot of trial and error, and a fair bit of frustration.
Curved puncture technique using a flexible stainless-steel needle in endoscopic ultrasound-guided hepaticogastrostomy
Authors: Haruo Miwa, Yuichi Suzuki, Shotaro Tsunoda, Kazuki Endo, Ritsuko Oishi, Hiromi Tsuchiya, Shin Maeda
Journal: Endoscopy (2024)

Puncturing the intrahepatic bile duct of segment 2 (B2) in an endoscopic ultrasound-guided hepaticogastrostomy (EUS-HGS) can be challenging when the bile duct is only accessible through the transesophageal route [1] [2]. In such cases, a flexible stainless-steel needle (SonoTip Pro Control 22G; Medi-Globe, Rosenheim, Germany) may provide a wider range of puncture angles [3]. We report a case of EUS-HGS performed using a 22-gauge stainless-steel needle in a patient in whom B2 puncture was challenging ([Video 1]).
Rescue endoscopic ultrasound-guided gastroenterostomy with closing of the duodenum in case of duodenal perforation
Authors: Meddy Dalex, Mariola Marx, Elodie Romailler, Sébastien Godat
Journal: Endoscopy (2024)

A duodenal perforation is a life-threatening condition [1] with a mortality rate between 8% to 25% [2]. We will present two cases of duodenal perforations managed endoscopically.
Submucosal tunnel endoscopic resection for removal of deep-seated rectal gastrointestinal stromal tumor in the muscularis propria
Authors: Shaotong Wang, Gangping Li, Jun Song
Journal: Endoscopy (2024)

Treatment of rectal gastrointestinal stromal tumors (GISTs) is complex, and surgical resection is recommended regardless of tumor size [1]. No definitive method has yet been established.
The stability of a novel 0.035-inch guidewire facilitates endoscopic ultrasound-guided hepaticoduodenostomy
Authors: Ritsuko Oishi, Haruo Miwa, Kazuki Endo, Hiromi Tsuchiya, Akihiro Funaoka, Yuichi Suzuki, Shin Maeda
Journal: Endoscopy (2024)

Endoscopic ultrasound-guided hepaticoduodenostomy (EUS-HDS) for the right posterior branch is an alternative technique to transpapillary drainage [1] [2]. However, insertion of a stent delivery system in EUS-HDS is challenging when the posterior branch and puncture route form an acute angle [3] [4]. A novel guidewire (CAPELLA 0.035; Japan Lifeline Co., Ltd, Tokyo, Japan) has the advantage of high seeking ability due to a soft tapered tip, while the stiff shaft facilitates stent delivery ([Fig. 1]). Additionally, it can be used with most devices designed for 0.025-inch guidewires ([Video 1]).
Bispecific antibodies targeting BCMA or GPRC5D are highly effective in relapsed myeloma after CAR T-cell therapy
Authors: Maximilian Merz, Danai Dima, Hamza Hashmi, Nausheen Ahmed, Friedrich Stölzel, Tobias A. W. Holderried, Roland Fenk, Fabian Müller, Natalia Tovar, Aina Oliver-Cáldes, Kristin Rathje, James A. Davis, David Fandrei, Vladan Vucinic, Soraya Kharboutli, Ben-Niklas Baermann, Francis Ayuk, Uwe Platzbecker, Anca-Maria Albici, Nathalie Schub, Friederike Schmitz, Leyla Shune, Jack Khouri, Faiz Anwer, Shahzad Raza, Joseph McGuirk, Zahra Mahmoudjafari, Kimberly Green, Cyrus Khandanpour, Marcel Teichert, Barbara Jeker, Michele Hoffmann, Nicolaus Kröger, Bastian von Tresckow, Carlos Fernández de Larrea, Thomas Pabst, Al-Ola Abdallah, Nico Gagelmann
Journal: Blood Cancer Journal (2024)

Abstract Despite the astonishing outcomes after chimeric antigen receptor (CAR) T-cell therapy for relapsed refractory multiple myeloma (RRMM), most patients eventually relapse. There are only limited data available on salvage therapies following relapse after BCMA-directed CAR T-cell therapy. Here, we analyzed outcomes of post-CAR T-cell therapy relapse and impact of different salvage strategies in an international cohort of 139 patients ( n = 130 ide-cel, n = 9 cilta-cel), receiving talquetamab ( n = 28), teclistamab ( n = 37), combinations of immunomodulating drugs (IMiDs), proteasome inhibitors (PIs) or CD38 monoclonal antibodies ( n = 43), and others ( n = 31). The median time to relapse after CAR T-cell therapy was 5 months, 53% had the extramedullary disease (EMD) at relapse, associated with dismal post-relapse outcome ( P = 0.005). Overall response and complete response upon salvage therapies were 79% and 39% for talquetamab, 64% and 32% for teclistamab, 30% and 0% for IMiDs/PIs/CD38, and 26% and 3% for others ( P &lt; 0.001). Duration of response, as well as median survival, was significantly improved with bispecific antibodies ( P &lt; 0.001, respectively). Bispecific antibodies seemed to overcome the poor prognosis associated with early relapse and EMD, and were independent predictors for improved survival in multivariable analysis. In summary, these results suggest bispecific antibodies as the standard of care for relapse after CAR T-cell therapy for RRMM.
The association between rickettsial infection and hyperinflammation, diagnostic and management challenges.
Authors: Sophie Skarbek, Thomas HA Samuels,, Sana Sharrack, Danielle Cohen, Jessica J. Manson, Rachel S. Tattersall, Michael Brown, James E. Meiring
Journal: Journal of Infection (2024)

Highlights•There is an increasing recognition in the literature of the association between rickettsial infection and a hyperinflammatory state.•Ferritin is a useful proxy marker of hyperinflammation, and along with persistent fever and falling blood counts should prompt consideration of haemophagocytic lymphohistiocytosis.•Clinical diagnosis and management is challenging in this patient cohort, therefore multidisciplinary working is essential when considering immunomodulation therapy.
Prevalence of depression in pediatric patients with diagnosed or at high risk for obstructive sleep apnea: A systematic review with meta-analysis
Authors: Lara Pereira, Ellen Song, Cristine M Stefani, Carlos Flores-Mir, Graziela De Luca Canto, Camila Pacheco-Pereira
Journal: Sleep Medicine Reviews (2024)

Obstructive sleep apnea (OSA) may increase the risk of depression through various hypothesized mechanisms. Studies regarding this relationship with children are limited. This systematic review aims to assess the prevalence of depression in pediatric patients with OSA. Five electronic databases, grey literature, and reference lists of included studies were systematically searched. Studies reporting the prevalence of depression, as described by the Diagnostic and Statistical Manual of Mental Disorders (DSM), psychiatric evaluation or other validated screening measures, in children with OSA diagnosed by polysomnography (PSG), or at high risk for OSA based on positive scores on other validated measures were included. The risk of bias was performed using the Joanna Briggs Institute (JBI) Checklist for cross-sectional studies. Six studies from three countries and over 2300 pediatric patients were included. This meta-analysis showed an overall 28 % prevalence of depression among children with OSA or at high risk for OSA, which is almost two-fold higher than among children without OSA (controls). Overall, this meta-analysis suggests that around one out of every four children with or at high risk for OSA could have depression, and one in 10 children if OSA has been confirmed by PSG. Screening of OSA in pediatric patients with symptoms of depression and vice versa, screening of depressive symptoms in children with suspected or confirmed OSA, may be valuable areas of focus for multidisciplinary preventative care to optimize psychiatric treatment.
Probing the limits and capabilities of diffusion models for the anatomic editing of digital twins
Authors: Karim Kadry, Shreya Gupta, Farhad R. Nezami, Elazer R. Edelman
Journal: npj Digital Medicine (2024)

Numerical simulations of cardiovascular device deployment within digital twins of patient-specific anatomy can expedite and de-risk the device design process. Nonetheless, the exclusive use of patient-specific data constrains the anatomic variability that can be explored. We study how Latent Diffusion Models (LDMs) can edit digital twins to create digital siblings. Siblings can serve as the basis for comparative simulations, which can reveal how subtle anatomic variations impact device deployment, and augment virtual cohorts for improved device assessment. Using a case example centered on cardiac anatomy, we study various methods to generate digital siblings. We specifically introduce anatomic variation at different spatial scales or within localized regions, demonstrating the existence of bias toward common anatomic features. We furthermore leverage this bias for virtual cohort augmentation through selective editing, addressing issues related to dataset imbalance and diversity. Our framework delineates the capabilities of diffusion models in synthesizing anatomic variation for numerical simulation studies.
Leveraging a Vision Transformer Model to Improve Diagnostic Accuracy of Cardiac Amyloidosis With Cardiac Magnetic Resonance
Authors: Joshua Cockrum, Makiya Nakashima, Carl Ammoury, Diane Rizkallah, Joseph Mauch, David Lopez, David Wolinksy, Tae Hyun Hwang, Samir Kapadia, Lars G Svensson, Richard Grimm, Mazen Hanna, W H Wilson Tang, Christopher Nguyen, David Chen, Deborah Kwon
Journal: JACC. Cardiovascular imaging (2024)