tbuckley/cabot-search huggingface dataset:
DLL3-guided therapies in small-cell lung cancer: from antibody-drug conjugate to precision immunotherapy and radioimmunotherapy
Authors: Po-Lan Su, Karthik Chakravarthy, Naoki Furuya, Jeremy Brownstein, Jianhua Yu, Meixiao Long, David Carbone, Zihai Li, Kai He
Journal: Molecular Cancer (2024)

Abstract DLL3 acts as an inhibitory ligand that downregulates Notch signaling and is upregulated by ASCL1, a transcription factor prevalent in the small-cell lung cancer (SCLC) subtype SCLC-A. Currently, the therapeutic strategies targeting DLL3 are varied, including antibody-drug conjugates (ADCs), bispecific T-cell engagers (BiTEs), and chimeric antigen receptor (CAR) T-cell therapies. Although rovalpituzumab tesirine (Rova-T) showed promise in a phase II study, it failed to produce favorable results in subsequent phase III trials, leading to the cessation of its development. Conversely, DLL3-targeted BiTEs have garnered significant clinical interest. Tarlatamab, for instance, demonstrated enhanced response rates and progression-free survival compared to the standard of care in a phase II trial; its biologics license application (BLA) is currently under US Food and Drug Administration (FDA) review. Numerous ongoing phase III studies aim to further evaluate tarlatamab’s clinical efficacy, alongside the development of novel DLL3-targeted T-cell engagers, both bispecific and trispecific. CAR-T cell therapies targeting DLL3 have recently emerged and are undergoing various preclinical and early-phase clinical studies. Additionally, preclinical studies have shown promising efficacy for DLL3-targeted radiotherapy, which employs β-particle-emitting therapeutic radioisotopes conjugated to DLL3-targeting antibodies. DLL3-targeted therapies hold substantial potential for SCLC management. Future clinical trials will be crucial for comparing treatment outcomes among various approaches and exploring combination therapies to improve patient survival outcomes.
Genomic landscape of CCUS compared to MDS and its implications on risk prediction
Authors: Sandra Huber, Constance Baer, Stephan Hutter, Natalie Wossidlo, Gregor Hoermann, Christian Pohlkamp, Wencke Walter, Manja Meggendorfer, Wolfgang Kern, Torsten Haferlach, Claudia Haferlach
Journal: Leukemia (2024)
Comprehensive Characterization of the Integrin Family Across 32 Cancer Types
Authors: Cheng Zou, Jinwei Zhu, Jiangling Xiong, Yu Tian, Yousong Peng, Edwin Cheung, Dingxiao Zhang
Journal: Genomics Proteomics & Bioinformatics (2024)

Integrin genes are widely involved in tumorigenesis. Yet, a comprehensive characterization of integrin family members and their interactome at the pan-cancer level is lacking. Here, we systematically analyzed integrin family in approximately 10,000 tumors across 32 cancer types. Globally, integrins represent a frequently altered and misexpressed pathway, with alteration and dysregulation overall being protumorigenic. Expression dysregulation, better than mutational landscape, of integrin family successfully identifies a subgroup of aggressive tumors with a high level of proliferation and stemness. The results reveal that several molecular mechanisms collectively regulate integrin expression in a context-dependent manner. For potential clinical usage, we constructed a weighted scoring system, integrinScore, to measure integrin signaling patterns in individual tumors. Remarkably, integrinScore was consistently correlated with predefined molecular subtypes in multiple cancers, with integrinScore-high tumors being more aggressive. Importantly, integrinScore was cancer-dependent and closely associated with proliferation, stemness, tumor microenvironment, metastasis, and immune signatures. IntegrinScore also predicted patients' response to immunotherapy. By mining drug databases, we unraveled an array of compounds that may modulate integrin signaling. Finally, we built a user-friendly database, Pan-cancer Integrin Explorer (PIExplorer; http://computationalbiology.cn/PIExplorer), to facilitate researchers to explore integrin-related knowledge. Collectively, we provide a comprehensive characterization of integrins across cancers and offer gene-specific and cancer-specific rationales for developing integrin-targeted therapy.
Impact of heart failure hospitalizations on clinical outcomes after mitral transcatheter edge‐to‐edge repair: Results from the EXPAND study
Authors: Mirjam Kessler, Wolfgang Rottbauer, Ralph Stephan von Bardeleben, Carmelo Grasso, Philipp Lurz, Paul Mahoney, Matthew Price, Mathew Williams, Paolo Denti, Rodrigo Estevez‐Loureiro, Saibal Kar, Francesco Maisano
Journal: European Journal of Heart Failure (2024)

Abstract Aim This analysis aimed to compare the clinical outcomes associated with heart failure (HF) readmissions and to identify associations with HF hospitalizations (HFH) in patients treated with the MitraClip™ NTR/XTR System in the EXPAND study. Methods and results The global, real‐world EXPAND study enrolled 1041 patients with primary or secondary mitral regurgitation (MR) treated with the MitraClip NTR/XTR System. Echocardiograms were analysed by an independent echocardiographic core laboratory. The study population was stratified into HFH and No‐HFH groups based on the occurrence of HFH 1 year post‐index procedure. Clinical outcomes including MR severity, New York Heart Association (NYHA) functional class, Kansas City Cardiomyopathy Questionnaire (KCCQ) score, and all‐cause mortality were compared (HFH: n = 181; No‐HFH: n = 860). Both groups achieved consistent 1‐year MR reduction to ≤1+ (HFH vs. No‐HFH: 87.3% vs. 89.5%, p = 0.6) and significant 1‐year improvement in KCCQ scores (+16.5 vs. +22.3, p = 0.09) and NYHA functional class. However, more patients in the No‐HFH group had 1‐year NYHA class ≤II (HFH vs. No‐HFH: 67.9% vs. 81.9%, p &lt; 0.01). All‐cause mortality at 1 year was 36.8% in the HFH group versus 10.4% in the No‐HFH group ( p &lt; 0.001). The HFH rate decreased by 63% at 1 year post‐M‐TEER versus 1 year pre‐treatment (relative risk 0.4, p &lt; 0.001). Independent HFH associations were MR ≥2+ at discharge, HFH 1 year prior to treatment, baseline NYHA class ≥III, baseline tricuspid regurgitation ≥2+, and baseline left ventricular ejection fraction ≤40%. Conclusions This study reports the impact of HFH on clinical outcomes post‐treatment in the EXPAND study. Results demonstrate that the occurrence of HFH was associated with worse 1‐year survival, and treatment with the MitraClip system substantially reduced HFH and improved patient symptoms and quality of life.
Biofilms and core pathogens shape the tumor microenvironment and immune phenotype in colorectal cancer
Authors: Lasse Kvich, Blaine Gabriel Fritz, Henrike Zschach, Thilde Terkelsen, Hans Raskov, Kathrine Høst-Rasmussen, Morten Ragn Jakobsen, Alexandra Gabriella Gheorghe, Ismail Gögenur, Thomas Bjarnsholt
Journal: Gut Microbes (2024)

Extensive research has explored the role of gut microbiota in colorectal cancer (CRC). Nonetheless, metatranscriptomic studies investigating the in situ functional implications of host-microbe interactions in CRC are scarce. Therefore, we characterized the influence of CRC core pathogens and biofilms on the tumor microenvironment (TME) in 40 CRC, paired normal, and healthy tissue biopsies using fluorescence in situ hybridization (FISH) and dual-RNA sequencing. FISH revealed that Fusobacterium spp. was associated with increased bacterial biomass and inflammatory response in CRC samples. Dual-RNA sequencing demonstrated increased expression of pro-inflammatory cytokines, defensins, matrix-metalloproteases, and immunomodulatory factors in CRC samples with high bacterial activity. In addition, bacterial activity correlated with the infiltration of several immune cell subtypes, including M2 macrophages and regulatory T-cells in CRC samples. Specifically, Bacteroides fragilis and Fusobacterium nucleatum correlated with the infiltration of neutrophils and CD4+ T-cells, respectively. The collective bacterial activity/biomass appeared to exert a more significant influence on the TME than core pathogens, underscoring the intricate interplay between gut microbiota and CRC. These results emphasize how biofilms and core pathogens shape the immune phenotype and TME in CRC while highlighting the need to extend the bacterial scope beyond CRC pathogens to advance our understanding and identify treatment targets.
Minimal residual disease profiling predicts pathological complete response in esophageal squamous cell carcinoma
Authors: Pinli Yue, Fenglong Bie, Jiarun Zhu, Lin-Rui Gao, Zhendiao Zhou, Guangyu Bai, Xiaobing Wang, Ziyi Zhao, Ze-Fen Xiao, Yong Li, Aiping Zhou, Wen-Yang Liu, Yuchen Jiao, Shugeng Gao
Journal: Molecular Cancer (2024)

Abstract Accurate presurgical prediction of pathological complete response (pCR) can guide treatment decisions, potentially avoiding unnecessary surgeries and improving the quality of life for cancer patients. We developed a minimal residual disease (MRD) profiling approach with enhanced sensitivity and specificity for detecting minimal tumor DNA from cell-free DNA (cfDNA). The approach was validated in two independent esophageal squamous cell carcinoma (ESCC) cohorts. In a cohort undergoing neoadjuvant, surgical, and adjuvant therapy (NAT cohort), presurgical MRD status precisely predicted pCR. All MRD-negative cases (10/10) were confirmed as pCR by pathological evaluation on the resected tissues. In contrast, MRD-positive cases included all the 27 non-pCR cases and only one pCR case (10/10 vs 1/28, P &lt; 0.0001, Fisher’s exact test). In a definitive radiotherapy cohort (dRT cohort), post-dRT MRD status was closely correlated with patient prognosis. All MRD-negative patients (25/25) remained progression-free during the follow-up period, while 23 of the 26 MRD-positive patients experienced disease progression (25/25 vs 3/26, P &lt; 0.0001, Fisher’s exact test; progression-free survival, P &lt; 0.0001, log-rank test). The MRD profiling approach effectively predicted the ESCC patients who would achieve pCR with surgery and those likely to remain progression-free without surgery. This suggests that the cancer cells in these MRD-negative patients have been effectively eliminated and they could be suitable candidates for a watch-and-wait strategy, potentially avoiding unnecessary surgery.
The pattern theory of compassion
Authors: Shaun Gallagher, Antonino Raffone, Salvatore M. Aglioti
Journal: Trends in Cognitive Sciences (2024)

Concepts of empathy, sympathy and compassion are often confused in a variety of literatures. This article proposes a pattern-theoretic approach to distinguishing compassion from empathy and sympathy. Drawing on psychology, Western philosophy, affective neuroscience, and contemplative science, we clarify the nature of compassion as a specific pattern of dynamically related factors that include physiological, cognitive, and affective processes, relational/intersubjective processes, and motivational/action tendencies. We also show that the dynamic nature of the compassion pattern is reflected in neuroscientific findings, as well as in compassion practice. The pattern theory of compassion allows us to make several clear distinctions between compassion, empathy, and sympathy.
Reprogramming tumor-associated macrophages and inhibiting tumor neovascularization by targeting MANF-HSF1-HSP70-1 pathway: An effective treatment for hepatocellular carcinoma
Authors: Dan Han, Qiannan Ma, Petek Ballar, Chunyang Zhang, Min Dai, Xiaoyuan Luo, Jiong Gu, Chuansheng Wei, Panhui Guo, Lulu Zeng, Min Hu, Can Jiang, Yanyan Liang, Yanyan Wang, Chao Hou, Xian Wang, Lijie Feng, Yujun Shen, Yuxian Shen, Xiangpeng Hu, Jun Liu
Journal: Acta Pharmaceutica Sinica B (2024)

In advanced hepatocellular carcinoma (HCC) tissues, M2-like tumor-associated macrophages (TAMs) are in the majority and promotes HCC progression. Contrary to the pro-tumor effect of M2-like TAMs, M1-like TAMs account for a small proportion and have anti-tumor effects. Since TAMs can switch from one type to another, reprogramming TAMs may be an important treatment for HCC therapy. However, the mechanisms of phenotypic switch and reprogramming TAMs are still obscure. In this study, we analyzed differential genes in normal macrophages and TAMs, and found that loss of MANF in TAMs accompanied by high levels of downstream genes negatively regulated by MANF. MANF reprogrammed TAMs into M1 phenotype. Meanwhile, loss of MANF promoted HCC progression in HCC patients and mice HCC model, especially tumor neovascularization. Additionally, macrophages with MANF supplement suppressed HCC progression in mice, suggesting MANF supplement in macrophage was an effective treatment for HCC. Mechanistically, MANF enhanced the HSF1-HSP70-1 interaction, restricted HSF1 in the cytoplasm of macrophages, and decreased both mRNA and protein levels of HSP70-1, which in turn led to reprogramming TAMs, and suppressing neovascularization of HCC. Our study contributes to the exploration the mechanism of TAMs reprogramming, which may provide insights for future therapeutic exploitation of HCC neovascularization.
Screening antimicrobial peptides and probiotics using multiple deep learning and directed evolution strategies
Authors: Yu Zhang, Li-Hua Liu, Bo Xu, Zhiqian Zhang, Min Yang, Yiyang He, Jingjing Chen, Yang Zhang, Yucheng Hu, Xipeng Chen, Zitong Sun, Qijun Ge, Song Wu, Wei Lei, Kaizheng Li, Hua Cui, Gangzhu Yang, Xuemei Zhao, Man Wang, Jiaqi Xia, Zhen Cao, Ao Jiang, Yi-Rui Wu
Journal: Acta Pharmaceutica Sinica B (2024)

Owing to their limited accuracy and narrow applicability, current antimicrobial peptide (AMP) prediction models face obstacles in industrial application. To address these limitations, we developed and improved an AMP prediction model using Comparing and Optimizing Multiple DEep Learning (COMDEL) algorithms, coupled with high-throughput AMP screening method, finally reaching an accuracy of 94.8% in test and 88% in experiment verification, surpassing other state-of-the-art models. In conjunction with COMDEL, we employed the phage-assisted evolution method to screen Sortase in vivo and developed a cell-free AMP synthesis system in vitro, ultimately increasing AMPs yields to a range of 0.5‒2.1 g/L within hours. Moreover, by multi-omics analysis using COMDEL, we identified Lactobacillus plantarum as the most promising candidate for AMP generation among 35 edible probiotics. Following this, we developed a microdroplet sorting approach and successfully screened three L. plantarum mutants, each showing a twofold increase in antimicrobial ability, underscoring their substantial industrial application values.
Half‐life extension of single‐domain antibody–drug conjugates by albumin binding moiety enhances antitumor efficacy
Authors: Quanxiao Li, Yu Kong, Yuxuan Zhong, Ailing Huang, Tianlei Ying, Yanling Wu
Journal: MedComm (2024)

Abstract Single‐domain antibody–drug conjugates (sdADCs) have been proven to have deeper solid tumor penetration and intratumor accumulation capabilities due to their smaller size compared with traditional IgG format ADCs. However, one of the key challenges for improving clinical outcomes of sdADCs is their abbreviated in vivo half‐life. In this study, we innovatively fused an antihuman serum albumin (αHSA) nanobody to a sdADCs targeting oncofetal antigen 5T4, conferring serum albumin binding to enhance the pharmacokinetic profiles of sdADCs. The fusion protein was conjugated with monomethyl auristatin E (MMAE) at s224c site mutation. The conjugate exhibited potent cytotoxicity against various tumor cells. Compared with the nonalbumin‐binding counterparts, the conjugate exhibited a 10‐fold extended half‐life in wild‐type mice and fivefold prolonged serum half‐life in BxPC‐3 xenograft tumor models as well as enhanced tumor accumulation and retention in mice. Consequently, n501–αHSA–MMAE showed potent antitumor effects, which were comparable to n501–MMAE in pancreatic cancer BxPC‐3 xenograft tumor models; however, in human ovarian teratoma PA‐1 xenograft tumor models, n501–αHSA–MMAE significantly improved antitumor efficacy. Moreover, the conjugate showed mitigated hepatotoxicity. In summary, our results suggested that fusion to albumin‐binding moiety as a viable strategy can enhance the therapeutic potential of sdADCs through optimized pharmacokinetics.
Interleukin‐33 increases the sensitivity of multiple myeloma cells to the proteasome inhibitor bortezomib through reactive oxygen species‐mediated inhibition of nuclear factor kappa‐B signal and stemness properties
Authors: Ruonan Shao, Shuang Liu, Wenjian Liu, Cailu Song, Lingrui Liu, Lewei Zhu, Fu Peng, Yue Lu, Hailin Tang
Journal: MedComm (2024)

The proteasome inhibitor bortezomib (BTZ) is the first-line therapy for multiple myeloma (MM). BTZ resistance largely limits its clinical application in MM. Interleukin-33 (IL-33) exerts antitumor effects through various mechanisms, including enhancing antitumor immunity and promoting the apoptosis of cancer cells. Here, the synergistic anti-MM effect of IL-33 and BTZ was verified, and the underlying mechanisms were elucidated. Bioinformatic analysis indicated that IL-33 expression levels were downregulated in MM, and that BTZ-treated MM patients with high IL-33 levels had better prognosis than those with low IL-33 levels. Moreover, the patients with high IL-33 levels had a better treatment response to BTZ. Further immune analysis suggested that IL-33 can enhance the anti-MM immunity. IL-33 and BTZ synergistically inhibited proliferation and induced apoptosis of MM cells, which was mediated by the excessive accumulation of cellular reactive oxygen species (ROS). Furthermore, increased ROS hindered the nuclear translocation of NF-κB-p65, thereby decreasing the transcription of target stemness-related genes (
iPSC‐derived NK cells with site‐specific integration of CAR19 and IL24 at the multi‐copy rDNA locus enhanced antitumor activity and proliferation
Authors: Yuxuan Zhang, Qingxin Shi, Peiyun Wang, Chujun Huang, Shuqing Tang, Miaojin Zhou, Qian Hu, Lingqian Wu, Desheng Liang
Journal: MedComm (2024)

Abstract The generation of chimeric antigen receptor‐modified natural killer (CAR‐NK) cells using induced pluripotent stem cells (iPSCs) has emerged as one of the paradigms for manufacturing off‐the‐shelf universal immunotherapy. However, there are still some challenges in enhancing the potency, safety, and multiple actions of CAR‐NK cells. Here, iPSCs were site‐specifically integrated at the ribosomal DNA (rDNA) locus with interleukin 24 (IL24) and CD19‐specific chimeric antigen receptor (CAR19), and successfully differentiated into iPSC‐derived NK (iNK) cells, followed by expansion using magnetic beads in vitro. Compared with the CAR19‐iNK cells, IL24 armored CAR19‐iNK (CAR19‐IL24‐iNK) cells showed higher cytotoxic capacity and amplification ability in vitro and inhibited tumor progression more effectively with better survival in a B‐cell acute lymphoblastic leukaemia (B‐ALL) (Nalm‐6 (Luc1))‐bearing mouse model. Interestingly, RNA‐sequencing analysis showed that IL24 may enhance iNK cell function through nuclear factor kappa B (NFκB) pathway‐related genes while exerting a direct effect on tumor cells. This study proved the feasibility and potential of combining IL24 with CAR‐iNK cell therapy, suggesting a novel and promising off‐the‐shelf immunotherapy strategy.
Definition of diaphragmatic sleep disordered breathing and clinical meaning in Duchenne muscular dystrophy
Authors: Federica Trucco, Matthew Davies, Alberto Andrea Zambon, Deborah Ridout, Francois Abel, Francesco Muntoni
Journal: Thorax (2024)

Diaphragmatic sleep disordered breathing (dSDB) has been recently identified as sleep dysfunction secondary to diaphragmatic weakness in Duchenne muscular dystrophy (DMD). However, scoring criteria for the identification of dSDB are missing.This study aimed to define and validate dSDB scoring criteria and to evaluate whether dSDB severity correlates with respiratory progression in DMD.
Diet-microbiota associations in gastrointestinal research: a systematic review
Authors: Kerith Duncanson, Georgina Williams, Emily C. Hoedt, Clare E. Collins, Simon Keely, Nicholas J. Talley
Journal: Gut Microbes (2024)

Interactions between diet and gastrointestinal microbiota influence health status and outcomes. Evaluating these relationships requires accurate quantification of dietary variables relevant to microbial metabolism, however current dietary assessment methods focus on dietary components relevant to human digestion only. The aim of this study was to synthesize research on foods and nutrients that influence human gut microbiota and thereby identify knowledge gaps to inform dietary assessment advancements toward better understanding of diet-microbiota interactions. Thirty-eight systematic reviews and 106 primary studies reported on human diet-microbiota associations. Dietary factors altering colonic microbiota included dietary patterns, macronutrients, micronutrients, bioactive compounds, and food additives. Reported diet-microbiota associations were dominated by routinely analyzed nutrients, which are absorbed from the small intestine but analyzed for correlation to stool microbiota. Dietary derived microbiota-relevant nutrients are more challenging to quantify and underrepresented in included studies. This evidence synthesis highlights advancements needed, including opportunities for expansion of food composition databases to include microbiota-relevant data, particularly for human intervention studies. These advances in dietary assessment methodology will facilitate translation of microbiota-specific nutrition therapy to practice.
CD276 regulates the immune escape of esophageal squamous cell carcinoma through CXCL1–CXCR2 induced NETs
Authors: Gan Xiong, Zhi Chen, Qianwen Liu, Fang Peng, Caihua Zhang, Maosheng Cheng, Rongsong Ling, Shuang Chen, Yu Liang, Demeng Chen, Qimin Zhou
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background CD276 (B7-H3), a pivotal immune checkpoint, facilitates tumorigenicity, invasiveness, and metastasis by escaping immune surveillance in a variety of tumors; however, the underlying mechanisms facilitating immune escape in esophageal squamous cell carcinoma (ESCC) remain enigmatic. Methods We investigated the expression of CD276 in ESCC tissues from patients by using immunohistochemistry (IHC) assays. In vivo, we established a 4-nitroquinoline 1-oxide (4NQO)-induced CD276 knockout (CD276 wKO ) and K14cre; CD276 conditional knockout (CD276 cKO ) mouse model of ESCC to study the functional role of CD276 in ESCC. Furthermore, we used the 4NQO-induced mouse model to evaluate the effects of anti-CXCL1 antibodies, anti-Ly6G antibodies, anti-NK1.1 antibodies, and GSK484 inhibitors on tumor growth. Moreover, IHC, flow cytometry, and immunofluorescence techniques were employed to measure immune cell proportions in ESCC. In addition, we conducted single-cell RNA sequencing analysis to examine the alterations in tumor microenvironment following CD276 depletion. Results In this study, we elucidate that CD276 is markedly upregulated in ESCC, correlating with poor prognosis. In vivo, our results indicate that depletion of CD276 inhibits tumorigenesis and progression of ESCC. Furthermore, conditional knockout of CD276 in epithelial cells engenders a significant downregulation of CXCL1, consequently reducing the formation of neutrophil extracellular trap networks (NETs) via the CXCL1–CXCR2 signaling axis, while simultaneously augmenting natural killer (NK) cells. In addition, overexpression of CD276 promotes tumorigenesis via increasing NETs’ formation and reducing NK cells in vivo. Conclusions This study successfully elucidates the functional role of CD276 in ESCC. Our comprehensive analysis uncovers the significant role of CD276 in modulating immune surveillance mechanisms in ESCC, thereby suggesting that targeting CD276 might serve as a potential therapeutic approach for ESCC treatment.