tbuckley/cabot-search huggingface dataset:
RSK1 dependency in FLT3-ITD acute myeloid leukemia
Authors: Tim Kong, Angelo B. A. Laranjeira, Christopher T. Letson, LaYow Yu, Fan He, Aarthi Jayanthan, Gerrit Los, Sandra E. Dunn, Grant A. Challen, Stephen T. Oh
Journal: Blood Cancer Journal (2024)

Internal tandem duplications (ITD) in fms-like tyrosine kinase 3 (FLT3) represent the most common genetic alteration in de novo acute myeloid leukemia (AML). Here, we identify ribosomal protein s6 kinase a1 (RSK1) as a core dependency in FLT3-ITD AML and unveil the existence of crucial bi-directional regulation. RSK1 perturbation resulted in marked apoptosis and abrogated phosphorylation of FLT3 and associated downstream signaling cascades in FLT3-ITD AML cell lines. Using cycloheximide, MG-132, and ubiquitination assays, we further demonstrate mechanistically that RSK1 regulates FLT3-ITD activity, and protein stability through deubiqutinase USP1, which we identify as a second dependency. Importantly, multivariate analysis revealed heightened expression of RPS6KA1 and USP1 to be associated with poor patient prognosis, and these effectors may serve as biomarkers predictive of patient survival and therapeutic response to FLT3-ITD inhibitors. Lastly, RSK1 inhibition utilizing a first-in-class RSK inhibitor, PMD-026, that is currently undergoing Phase 2 development for breast cancer, diminished leukemic disease burden in MV4-11 xenograft and syngeneic Flt3ITDTet2KO leukemia models. These findings illustrate an unconventional and promising therapeutic strategy targeting FLT3-ITD leukemia.
Integrated analyses of multi-omic data derived from paired primary lung cancer and brain metastasis reveal the metabolic vulnerability as a novel therapeutic target
Authors: Hao Duan, Jianlan Ren, Shiyou Wei, Zhenyu Yang, Chuan Li, Zhenning Wang, Meichen Li, Zhi Wei, Yu Liu, Xiuqi Wang, Hongbin Lan, Zhen Zeng, Maodi Xie, Yuan Xie, Suwen Wu, Wanming Hu, Chengcheng Guo, Xiangheng Zhang, Lun Liang, Chengwei Yu, Yanhao Mou, Yu Jiang, Houde Li, Eric Sugarman, Rebecca A. Deek, Zexin Chen, Tao Li, Yaohui Chen, Maojin Yao, Likun Chen, Lunxu Liu, Gao Zhang, Yonggao Mou
Journal: Genome Medicine (2024)

Abstract Background Lung cancer brain metastases (LC-BrMs) are frequently associated with dismal mortality rates in patients with lung cancer; however, standard of care therapies for LC-BrMs are still limited in their efficacy. A deep understanding of molecular mechanisms and tumor microenvironment of LC-BrMs will provide us with new insights into developing novel therapeutics for treating patients with LC-BrMs. Methods Here, we performed integrated analyses of genomic, transcriptomic, proteomic, metabolomic, and single-cell RNA sequencing data which were derived from a total number of 154 patients with paired and unpaired primary lung cancer and LC-BrM, spanning four published and two newly generated patient cohorts on both bulk and single cell levels. Results We uncovered that LC-BrMs exhibited a significantly greater intra-tumor heterogeneity. We also observed that mutations in a subset of genes were almost always shared by both primary lung cancers and LC-BrM lesions, including TTN , TP53 , MUC16 , LRP1B , RYR2 , and EGFR . In addition, the genome-wide landscape of somatic copy number alterations was similar between primary lung cancers and LC-BrM lesions. Nevertheless, several regions of focal amplification were significantly enriched in LC-BrMs, including 5p15.33 and 20q13.33. Intriguingly, integrated analyses of transcriptomic, proteomic, and metabolomic data revealed mitochondrial-specific metabolism was activated but tumor immune microenvironment was suppressed in LC-BrMs. Subsequently, we validated our results by conducting real-time quantitative reverse transcription PCR experiments, immunohistochemistry, and multiplexed immunofluorescence staining of patients’ paired tumor specimens. Therapeutically, targeting oxidative phosphorylation with gamitrinib in patient-derived organoids of LC-BrMs induced apoptosis and inhibited cell proliferation. The combination of gamitrinib plus anti-PD-1 immunotherapy significantly improved survival of mice bearing LC-BrMs. Patients with a higher expression of mitochondrial metabolism genes but a lower expression of immune genes in their LC-BrM lesions tended to have a worse survival outcome. Conclusions In conclusion, our findings not only provide comprehensive and integrated perspectives of molecular underpinnings of LC-BrMs but also contribute to the development of a potential, rationale-based combinatorial therapeutic strategy with the goal of translating it into clinical trials for patients with LC-BrMs.
Monocyte transcriptome signatures of inflammation and enhanced neutrophil recruitment characterize immunopathology in the blood of TB patients
Authors: Hubert Senanu Ahor, Monika M Vivekanandan, Ernest Adankwah, Difery Minadzi, Isaac Acheampong, Wilfred Aniagyei, Augustine Yeboah, Joseph F Arthur, Millicent Lamptey, Mohammed K Abass, Francis Kumbel, Francis Osei-Yeboah, Amidu Gawusu, Patrick Petzsch, Karl Köhrer, Linda Batsa Debrah, Dorcas O Owusu, Alexander Debrah, Ertan Mayatepek, Julia Seyfarth, Richard O Phillips, Marc Jacobsen
Journal: Journal of Infection (2024)
Risk of invasive pneumococcal disease during pregnancy and postpartum and association with adverse maternal and foetal outcomes: a prospective cohort study, England, 2014-19
Authors: Zahin Amin-Chowdhury, Marta Bertran, Fariyo Abdullahi, Carmen L Sheppard, Seyi D Eletu, David J Litt, Norman K Fry, Shamez N Ladhani
Journal: Journal of Infection (2024)
The role of IL-1 family cytokines in diabetic cardiomyopathy
Authors: Qi Wu, Yan Zeng, Kang Geng, Man Guo, Fang-Yuan Teng, Pi-Jun Yan, Yi Lei, Yang Long, Zong-Zhe Jiang, Betty Yuen-Kwan Law, Yong Xu
Journal: Metabolism (2024)
Drofenine as a Kv2.1 inhibitor alleviated AD-like pathology in mice through Aβ/Kv2.1/microglial NLRP3/neuronal Tau axis
Authors: Jian Lu, Qian Zhou, Danyang Zhu, Hongkuan Song, Guojia Xie, Xuejian Zhao, Yujie Huang, Peng Cao, Jiaying Wang, Xu Shen
Journal: Acta Pharmaceutica Sinica B (2024)

Alzheimer's disease (AD) is a neurodegenerative disease with clinical hallmarks of progressive cognitive impairment. Synergistic effects of the Aβ-Tau cascade reaction are tightly implicated in AD pathology, and microglial NLRP3 inflammasome activation drives neuronal tauopathy. However, the underlying mechanism of how Aβ mediates NLRP3 inflammasome remains unclear. Herein, we determined that oligomeric Aβ (o-Aβ) bound to microglial Kv2.1 and promoted Kv2.1-dependent potassium efflux to activate NLRP3 inflammasome resulting in neuronal tauopathy by using Kv2.1 inhibitor drofenine (Dfe) as a probe. The underlying mechanism has been intensively investigated by assays with Kv2.1 knockdown in vitro (si-Kv2.1) and in vivo (AAV-ePHP-si-Kv2.1). Dfe deprived o-Aβ of its capability to promote microglial NLRP3 inflammasome activation and neuronal Tau hyperphosphorylation by inhibiting the Kv2.1/JNK/NF-κB pathway while improving the cognitive impairment of 5×FAD-AD model mice. Our results have highly addressed that the Kv2.1 channel is required for o-Aβ-driven microglial NLRP3 inflammasome activation and neuronal tauopathy in AD model mice and highlighted that Dfe as a Kv2.1 inhibitor shows potential in the treatment of AD.
Global, Regional, and National Burden of Spinal Cord Injury from 1990 to 2021 and Projections for 2050: a systematic analysis for the Global Burden of Disease 2021 Study
Authors: Yubao Lu, Zhizhong Shang, Wei Zhang, Xuchang Hu, Ruoqi Shen, Keni Zhang, Yuxin Zhang, Liangming Zhang, Bin Liu, Mao Pang, Limin Rong
Journal: Ageing Research Reviews (2024)
Comprehensive investigation of multiple targets in the development of newer drugs for the Alzheimer’s disease
Authors: Patil Ashwini, Bodhankar Subhash, Muthal Amol, Dileep Kumar, Pawar Atmaram, Kulkarni Ravindra
Journal: Acta Pharmaceutica Sinica B (2024)

Alzheimer's disease, a significant contributor to dementia, is rapidly becoming a serious healthcare concern in the 21st century. The alarming number of patients with Alzheimer's disease is steadily increasing, which is contributed by the dearth of treatment options. The current treatment for Alzheimer's disease is heavily dependent on symptomatic treatment that has failed to cure the disease despite huge investments in the development of drugs. The clinical treatment of Alzheimer's disease with limited drugs is generally targeted towards the inhibition of N-methyl-d-aspartate receptor and acetylcholine esterase, which only elevate cognition levels for a limited period. Beyond the aforementioned molecular targets, β-amyloid was much explored with little success and thus created a feel and palpable growing emphasis on discovering new putative and novel targets for AD. This has inspired medicinal chemists to explore new targets, including microglia, triggering receptors expressed on myeloid cells 2 (Trem-2), and notum carboxylesterase, to discover new lead compounds. This review explores the functions, pathophysiological roles, and importance of all AD-related targets that address therapeutic and preventive approaches for the treatment and protection of Alzheimer's disease.
Facilitation of mucosal healing by estrogen receptor β in ulcerative colitis through suppression of branched-chain amino acid transport and subsequent triggering of autophagy in colonic epithelial cells
Authors: Yilei Guo, Yanrong Zhu, Jing Zhang, Yue He, Mianjiang Zhao, Haochang Lin, Zhifeng Wei, Yufeng Xia, Yue Dai
Journal: Acta Pharmaceutica Sinica B (2024)

Colonic mucosal healing is the ultimate goal of ulcerative colitis (UC) treatment, but it remains difficult to realize. Given the higher incidence of UC in males and the beneficial effect of estrogen on UC, we conducted this study to examine the therapeutic potential of estrogen receptor β (ERβ), the primary ER subtype in colon, on mucosal healing in UC. Our study is the first to report that ERβ activation degree was positively correlated with mucosal healing in patients with UC. Furthermore, ERβ activation enhanced mucosal healing in mice with dextran sulfate sodium-induced and biopsy-induced colonic injuries. Mechanistically, ERβ activation promoted autophagy of colonic epithelial cells by inhibiting branched-chain amino acid transport, leading to focal adhesion kinase (FAK) activation. Activated FAK promoted focal adhesion turnover and colonic epithelial cell migration, ultimately facilitating mucosal healing. ERβ -/- colitis mice exhibited impaired mucosal healing compared to wild-type littermates, highlighting the crucial effect of ERβ. Importantly, combination with ERβ-agonist diarylpropionitrile enhanced the amelioration of 5-aminosalicylic acid, a standard UC treatment agent, against mouse colitis. These findings attest to the crucial role of ERβ activation in colonic mucosal healing and may further inform the development of novel strategies for UC treatment.
FGTI-2734 Inhibits ERK Reactivation to Overcome Sotorasib Resistance in KRAS G12C Lung Cancer
Authors: Aslamuzzaman Kazi, Hitesh Kumar Kantilal Vasiyani, Deblina Ghosh, Dipankar Bandyopadhyay, Rachit D Shah, Vignesh Vudatha, Jose Trevino, Said M Sebti
Journal: Journal of Thoracic Oncology (2024)
Amelioration of metabolic and behavioral defects through base editing in the PahR408W phenylketonuria mouse model
Authors: Shuming Yin, Liangcai Gao, Xiaoyue Sun, Mei Zhang, Hongyi Gao, Xiaoqing Chen, Dan Zhang, Xinyu Ming, Lei Yang, Yaqiang Hu, Xi Chen, Meizhen Liu, Xia Zhan, Yuting Guan, Liren Wang, Lianshu Han, Ping Zhu, Dali Li
Journal: Molecular Therapy (2024)
Comparison of Crohn’s disease-associated adherent-invasive <i>Escherichia coli</i> (AIEC) from France and Hong Kong: results from the Pacific study
Authors: Caroline Chevarin, Zhilu Xu, Lucas Martin, Frederic Robin, Racha Beyrouthy, Jean-Frédéric Colombel, Alexander Sulakvelidze, Siew C Ng, Richard Bonnet, Anthony Buisson, Nicolas Barnich
Journal: Gut Microbes (2024)

Association between ileal colonization by Adherent-Invasive Escherichia coli (AIEC) and Crohn's disease (CD) has been widely described in high-incidence Western countries but remains unexplored in Asian countries with a fast increase in CD incidence. In the PACIFIC study, we compared the characteristics of AIEC pathobionts retrieved from ileal biopsies of CD patients enrolled in France (FR) and Hong Kong (HK). The prevalence of AIEC was similar in France (24.5%, 25/102) and Hong Kong (30.0%, 18/60) (p = 0.44). No difference was observed between the two populations of AIEC regarding adhesion and invasion levels. When tested for antibiotic resistance, the proportion of AIEC strains resistant to ampicillin, piperacillin, tobramycin, and gentamicin was significantly higher in HK AIEC strains compared to French strains. AIEC strains from FR or HK population were both able to persist in the mice intestine (DSS-treated CEABAC10 mice model). Moreover, genomic analysis of 25 FR and 17 hK AIEC strains using next-generation sequencing revealed the co-existence of several virulence factors associated with enteric E. coli pathotypes, although no single virulence factor was significantly associated with either country of origin or AIEC status. In vitro, all AIEC strains (FR and HK) were sensitive to the EcoActive™ phage cocktail, suggesting that it could be a promising option to target AIEC in CD across the world.
Unusual FDG PET Appearances in a Patient With Metastatic Breast Carcinoma
Authors: Raima Kaleemi, Alexandra Dudek, Dimitris Priftakis, Jamshed Bomanji
Journal: Clinical Nuclear Medicine (2024)

Abstract This was a case of a 52-year-old woman with a history of multiorgan, metastatic breast cancer, who underwent several lines of treatment. She had brain metastases, which were treated with gamma knife. She progressed at other organ sites with additional recurrence of brain metastases and leptomeningeal disease, which demonstrated an interesting pattern of intracranial FDG uptake with further seizure-related muscular uptake.
18F-FDG PET/CT Imaging of Cutaneous and Intramuscular Multiple Myeloma
Authors: Brandon Lippold, Amin H. Jahromi
Journal: Clinical Nuclear Medicine (2024)

Abstract Cutaneous manifestations of multiple myeloma are rare but, as with other extramedullary manifestations, carry a worse prognosis. We present the case of a 65-year-old man with immunoglobulin G κ multiple myeloma and prior autologous stem cell transplant. On subsequent therapy, he presented with multiple new cutaneous and subcutaneous left hip masses. Biopsy of these lesions revealed plasma cell neoplasm with anaplastic morphology, confirming progression of disease. He subsequently underwent radiation to these lesions with plans for chimeric antigen receptor T-cell therapy due to refractory disease.
18F-FDG PET/CT Incidental Finding of Rare Extrapulmonary Presentation of Mycobacterium tuberculosis
Authors: Jennifer M. C. Ranes, Ana J. Ormaza, Charismas Desai, Sanjit O. Tewari, Lesley Flynt
Journal: Clinical Nuclear Medicine (2024)

Abstract A 41-year-old woman presented with a left breast mass for which mammography was performed. Mammogram revealed a suspicious BI-RADS 4, palpable left breast mass with associated nipple retraction. As malignancy was suspected, the patient underwent breast MRI and 18 F-FDG PET/CT for staging. Multiple ultrasound guided biopsies were then performed of the left breast, left axillary lymph nodes, and left cervical lymph nodes. Final pathology was negative for malignancy, but final cultures grew Mycobacterium tuberculosis (Tb). The patient was initially intolerant to frontline medications, but eventually successfully treated with isoniazid, ethambutol, pyrazinamide, and moxifloxacin, as demonstrated by posttreatment mammography.
“Motion Capture Suit Sign” for Immunotherapy-Induced Inflammatory Arthritis on 99mTc-MDP Bone Scintigraphy
Authors: Dallas Shun-Yu Yew, Chun-Liang Lai
Journal: Clinical Nuclear Medicine (2024)

Abstract We report the 99m Tc-MDP bone scan of a 44-year-old man with a history of lung adenocarcinoma and recent multiple joint pain after completing pembrolizumab immunotherapy treatment. This interesting image of symmetric uptakes around bilateral joints throughout the skeleton resembles the ball sensors on a motion capture suit. Hence, we recommend naming this distinctive imaging appearance as the “motion capture suit” sign.
Basal Cell Carcinoma of the Head With Intense [68Ga]OncoFAP Uptake
Authors: David Ventura, Iris Ernst, Barbara Timma, Michael Schäfers, Philipp Backhaus
Journal: Clinical Nuclear Medicine (2024)

Abstract A 72-year-old man with advanced locally invasive basal cell carcinoma of the forehead failed several pretreatments including surgery and radiation. MRI was not feasible because of the presence of facial implants. CT scan did not provide clear evidence of vital/avital tumor sites as a result of slow progression and previous radiation treatments. Due to limited treatment options, the patient underwent evaluation with 68 Ga-OncoFAP PET/CT for potential stereotactic body radiation therapy. We present a rare case of advanced and metastasized basal cell carcinoma with vigorous FAP (fibroblast activation protein) expression.
Diffuse Peritoneal Carcinomatosis of Prostate Cancer Unveiled by [89Zr]Zr-PSMA-617 PET/CT
Authors: Moritz B. Bastian, Caroline Burgard, Arne Blickle, Samer Ezziddin, Florian Rosar
Journal: Clinical Nuclear Medicine (2024)

We report an interesting case of a 64-year-old man with a history of radical prostatectomy for prostate cancer. The patient presented with steady increasing prostate-specific antigen levels, but with negative findings on previous multiple conventional prostate-specific membrane antigen (PSMA) PET/CT (with [68Ga]Ga-PSMA-11) and [18F]FDG PET/CT. A recently introduced PSMA tracer using long-lived 89Zr (half-life 3.3 days), [89Zr]Zr-PSMA-617, was administered in attempt to localize potential local recurrence or metastasis. [89Zr]Zr-PSMA-617 PET/CT clearly revealed diffuse peritoneal carcinomatosis and local recurrence of the prostate cancer, which were unidentified on previous conventional PET/CT scans. This case highly demonstrates the potential of PET imaging with the novel PSMA tracer [89Zr]Zr-PSMA-617.
Corrigendum to “Gold core@CeO2 halfshell Janus nanocomposites catalyze targeted sulfate radical for periodontitis therapy” [Journal of Controlled Release 370 (2024) 600–613]
Authors: Sijia Li, Qihang Ding, Lingling Zhang, Fangyu Shi, Chengyu Liu, Tingxuan Li, Yujia Shi, Manlin Qi, Lin Wang, Biao Dong, Shuyan Song, Jiao Sun, Jong Seung Kim, Chunyan Li
Journal: Journal of Controlled Release (2024)
Modified endoscopic hand-suturing without scope reinsertion for an ileocecal defect after endoscopic submucosal dissection
Authors: Lizhou Dou, Shibo Song, Chen Zhang, Yumeng Liu, Ying Lv, Guiqi Wang
Journal: Endoscopy (2024)

We present a modified endoscopic hand-suturing (EHS) technique that effectively and safely closed an ileocecal defect following endoscopic submucosal dissection (ESD) without requiring reinsertion of the endoscope. A 59-year-old woman underwent ESD for a laterally spreading tumor measuring approximately 3.5 × 3.0 cm in the ileocecum. The steps of the modified EHS procedure are detailed below ([Video 1]).
How the Versatile Self‐Assembly in Drug Delivery System to Afford Multimodal Cancer Therapy?
Authors: Yuqi Cao, Xiaomin Zhao, Yuhang Miao, Xin Wang, Dawei Deng
Journal: Advanced Healthcare Materials (2024)

The rapid development of self-assembly technology during the past few decades has effectively addressed plenty of the issues associated with carrier-based drug delivery systems, such as low loading efficiency, complex fabrication processes, and inherent toxicity of carriers. The integration of nanoscale delivery systems with self-assembly techniques has enabled efficient and targeted self-administration of drugs, enhanced bioavailability, prolonged circulation time, and controllable drug release. Concurrently, the limitations of single-mode cancer treatment, including low bioavailability, poor therapeutic outcomes, and significant side effects, have highlighted the urgent need for multimodal combined antitumor therapies. Set against the backdrop of multimodal cancer therapy, this review summarizes the research progress and applications of a large number of self-assembled drug delivery platforms, including natural small molecule self-assembled, carrier-free self-assembled, amphiphilic polymer-based self-assembled, peptide-based self-assembled, and metal-based self-assembled nano drug delivery systems. This review particularly analyzes the latest advances in the application of self-assembled nano drug delivery platforms in combined antitumor therapies mediated by chemotherapy, phototherapy, radiotherapy, sonodynamic therapy, and immunotherapy, providing innovative research insights for further optimization and expansion of self-assembled nano drug delivery systems in the clinical translation and development of antitumor combined therapy.
Antitumor Activity of a Bispecific Chimera Targeting EGFR and Met in Gefitinib‐Resistant Non‐Small Cell Lung Cancer
Authors: Ya Wang, Guixi Zhang, Zhilan Zhou, Ning Zhang, Hang Jiang, Yichang Liu, Ting Fu, Yingdi Zhu, Juan Li
Journal: Advanced Healthcare Materials (2024)

Abstract Non‐small cell lung cancers (NSCLC) frequently acquire resistance to tyrosine kinase inhibitors (TKI) due to epidermal growth factor receptor (EGFR) mutation or activation of the bypass pathway involving mesenchymal‐epithelial transition factor (Met). To address this challenge, a bispecific nanobody‐aptamer chimera is designed to target mutated EGFR and Met simultaneously to block their cross‐talk in NSCLC. The EGFR‐Met chimera is cost‐effectively engineered using microbial transglutaminase and click chemistry strategies. With enhanced binding affinity toward the target proteins, the as‐developed chimera inhibits efficiently the cross‐talk between signaling pathways associated with EGFR and Met. This inhibition leads to the suppression of downstream pathways, such as Erk and Akt, and induces upregulation of cell cycle arrest‐related proteins, including Rb, p21, and p27. Additionally, the chimera activates the caspase‐dependent apoptotic signaling pathway. Consequently, it inhibits cell migration, induces cell death, and causes cell cycle arrest in vitro. Moreover, the chimera exhibits significant antitumor efficacy in drug‐resistant xenograft mouse models, showcasing improved tissue penetration and low toxicity. This study accentuates the potential of the bispecific EGFR‐Met chimera as a promising therapeutic option for NSCLC resistant to EGFR TKIs.
Successful endoscopic sphincterotomy using a novel rotatable sphincterotome in a patient with Roux-en-Y gastrectomy
Authors: Yuki Tanisaka, Shomei Ryozawa, Masafumi Mizuide, Akashi Fujita, Ryuhei Jinushi, Ryuichi Watanabe, Ryo Sato
Journal: Endoscopy (2024)

Balloon enteroscopy-assisted endoscopic retrograde cholangiopancreatography (ERCP) is reported to be useful for patients with Roux-en-Y gastrectomy [1] [2] [3]. However, performing endoscopic sphincterotomy (EST) is considered challenging because the papilla appears inverted and its position is often tangential, which makes visualizing the correct direction for the incision (5 o'clock direction) difficult. Although there are several sphincterotomes facilitating EST in such cases, they do not always ensure the correct direction for EST [4] [5].
Master–apprentice technique for improved learning of endoscopic closure of defects using the reopenable clip-over-line method
Authors: Akihiro Maruyama, Tatsuma Nomura, Hirotaka Takeshima, Hiroshi Nakayabu, Hiroki Kato, Shintaro Tominaga, Makoto Kobayashi
Journal: Endoscopy (2024)

Various methods for endoscopic closure of defects have been recently developed [1]. The reopenable clip-over-line method (ROLM) is a novel defect closure technique [2] [3] [4], and we have developed a master–apprentice approach to improve training in this method [5].