tbuckley/cabot-search huggingface dataset:
Inflammasome-Activating Nanovaccine for Cancer Immunotherapy
Authors: Wenyao Zhen, Xiaoyuan Chen
Journal: Cancer Research (2024)

A range of advanced nanovaccines (NV) combined with immunotherapies has recently emerged for treating malignant tumors and has demonstrated promising tumor-suppressive effects. Nevertheless, their effectiveness is often limited by immunosuppression within the tumor microenvironment. To overcome this challenge, new approaches for NV development are required to improve antigen cross-presentation and to remodel the tumor microenvironment. In this issue of Cancer Research, Zhou and colleagues have developed a photo-enhanceable inflammasome-activating nanovaccine (PIN) designed for precise, in situ delivery of a tumor antigen and a hydrophobic small molecule that activates the NLRP3 inflammasome pathway. Near infrared light exposure enables the accumulation of PINs at tumor sites by inducing a photo-triggered charge reversal in the BODIPY-modified PAMAM nanocarrier. Systemic administration of PINs resulted in effective intratumoral activation of the NLRP3 inflammasome and antigen cross-presentation in antigen-presenting cells upon light exposure, leading to enhanced immune responses through increased proinflammatory cytokine production without significant systemic toxicity. Importantly, PINs also enhanced the efficacy of immune checkpoint blockade and promoted the development of long-term immune memory in mouse models of melanoma and hepatocellular carcinoma. Overall, inflammasome-activating NVs represent a cancer immunotherapy strategy by harnessing the innate immune system to achieve robust responses against tumors. Ongoing research and development are crucial to addressing current limitations and advancing this innovative technology toward clinical application. See related article by Zhou et al., p. 3834.
Chemoradiotherapy and Subsequent Immunochemotherapy as Conversion Therapy in Unresectable Locally Advanced Esophageal Squamous Cell Carcinoma: A Phase II NEXUS-1 Trial
Authors: Xin Wang, Xiaozheng Kang, Ruixiang Zhang, Liyan Xue, Jiaqi Xu, Xiaotian Zhao, Qiuxiang Ou, Nuo Yu, Guojie Feng, Jiao Li, Ziyu Zheng, Xiankai Chen, Zhen Wang, Qingfeng Zheng, Yong Li, Jianjun Qin, Nan Bi, Yin Li
Journal: Clinical Cancer Research (2024)

Abstract Purpose: This phase II trial investigated the safety and efficacy of chemoradiotherapy (CRT) followed by immunochemotherapy (iCT) and surgery in unresectable locally advanced esophageal squamous cell carcinoma (ESCC). Patients and Methods: Patients with unresectable locally advanced ESCC received radiotherapy (50 Gy/25f, 5 days/week) and nab-paclitaxel (100 mg on day 1/week) plus cisplatin (25 mg/m2 on day 1/week) for 5 weeks, followed by tislelizumab (200 mg on day 1/cycle) plus chemotherapy (nab-paclitaxel 150 mg/m2 and cisplatin 75 mg/m2 on day 2/cycle) for two 21-day cycles. Patients who converted to resectable underwent surgery 2 to 4 weeks afterward. The primary endpoint was a 1-year progression-free survival (PFS) rate. Results: Thirty patients were enrolled and underwent CRT (median follow-up: 21 months), of whom 24 received iCT. Twenty (66.7%) patients achieved resectability (R0: 95.2%; pathologic complete response: 65.0%; major pathologic response: 90.0%). One-year PFS and overall survival (OS) rates were 79.4% and 89.6%, respectively. The R0 resection group exhibited longer PFS (median, not reached vs. 8.4 months; HR = 0.28; 95% confidence interval, 0.08–0.84; P = 0.02) and OS (median, not reached vs. 19.2 months; HR = 0.18; 95% confidence interval, 0.04–0.73; P &amp;lt; 0.01) than the nonsurgery group. Grade 3 to 4 adverse events were observed in 11 (11/30, 36.7%) patients, and immune-related pneumonitis was observed in 5 (5/24, 20.8%) patients. Post-CRT minimal residual disease before surgery was associated with unfavorable PFS and OS. Conclusions: Our study met the primary endpoint. Conversion CRT and subsequent iCT followed by surgery was a promising treatment strategy for unresectable locally advanced ESCC.
The tissue and circulating cell‐free DNA‐derived genetic landscape of premalignant colorectal lesions and its application for early diagnosis of colorectal cancer
Authors: Qingjian Chen, Yu‐Hong Xu, Shiyang Kang, WuHao Lin, Linna Luo, Luping Yang, Qi‐Hua Zhang, Pan Yang, Jia‐Qian Huang, Xiaoni Zhang, Jing Zhang, Qi Zhao, Rui‐Hua Xu, Hui‐Yan Luo
Journal: MedComm (2024)

Abstract Colorectal adenomas (CRAs) represent precancerous lesions that precede the development of colorectal cancer (CRC). Regular monitoring of CRAs can hinder the progression into carcinoma. To explore the utility of tissue DNA and circulating cell‐free DNA (cfDNA) in early diagnosis of CRC, we retrospectively sequenced paired tissue and plasma samples from 85 patients with conventional CRAs. The genetic alterations identified were compared with those from 78 stage‐I CRC patients (CRC‐I) in the ChangKang project. Within the CRA cohort, we pinpointed 12 genes, notably APC , KRAS , and SOX9 , that exhibited significant mutated rates in tissue. Patients harboring KMT2C and KMT2D mutations displayed persistent polyps. By comparing with the mutational profiles of metastatic CRC plasma samples, we found that ZNF717 was exclusively mutated in CRAs, while KMT2C and KMT2D mutations were detected in both CRA and CRC. The presence of cfDNA mutations in plasma was validated through polymerase chain reaction, enhancing the feasibility of using cfDNA mutations for early CRC screening. Compared with CRC‐I, CRAs exhibited a reduced frequency of TP53 and PIK3CA somatic mutations and underwent non‐neutral evolution more often. We established a random forest model based on 15 characteristic genes to distinguish CRA and CRC, achieving an area under the curve of 0.89. Through this endeavor, we identified two novel genes, CNTNAP5 and GATA6 , implicated in CRC carcinogenesis. Overall, our findings reveal convincing biomarkers markers for detecting CRAs with a propensity for CRC development, highlighting the importance of early genetic screening in CRC prevention.
Genetically Engineered Bacteria as A Living Bioreactor for Monitoring and Elevating Hypoxia‐Activated Prodrug Tumor Therapy
Authors: Hongwei Zhang, Linfu Chen, Qian Chen, Qiufang Chen, Jun Zhou
Journal: Advanced Healthcare Materials (2024)

Abstract Tirapazamine (TPZ), an antitumor prodrug, can be activated in hypoxic environment. It specifically targets the hypoxic microenvironment of tumors and produces toxic free radicals. However, due to the tumor is not completely hypoxic, TPZ often fails to effectively treat the entire tumor tissue, resulting in suboptimal therapeutic outcomes. Herein, a low pathogenic Escherichia coli TOP10 is utilized to selectively colonize tumor tissues, disrupt blood vessels, and induce thrombus formation, leading to the expansion of hypoxic region and improving the therapeutic effect of TPZ. Additionally, a thermosensitive hydrogel is constructed by Pluronic F‐127 (F127), which undergoes gelation in situ at the tumor site, resulting in sustained release of TPZ. To monitor the therapeutic process, it is genetically modified TOP10 by integrating the bioluminescent system luxCDABE (TOP10‐Lux). The bioluminescent signal is associated with tumor hypoxia enhancement and thrombus formation, which is beneficial for therapeutic monitoring with bioluminescence imaging. In the murine colon cancer model, the TOP10‐Lux combined with TPZ‐loaded F127 hydrogel effectively suppressed tumor growth, and the treatment process is efficiently monitored. Together, this work employs genetically modified TOP10‐Lux to enhance the therapeutic efficacy of TPZ and monitor the treatment process, providing an effective strategy for bacteria‐based tumor‐targeted chemotherapy and treatment monitoring.
Fe/Cu Bimetallic Nanozyme Co‐Assembled with <sup>177</sup>Lu and Tanshinone for Quadruple‐Synergistic Tumor‐Specific Therapy
Authors: Xianyu Zhu, Lingling Zheng, Pengfei Zhao, Lingli Gao, Liang Wang, Jun Liu, Xu Yang, Hanrui Wei, Mingyu Zhang, Liang Yan, Han Lv, Jianhua Gong, Ji gang Yang, Zhenchang Wang
Journal: Advanced Healthcare Materials (2024)

Abstract The co‐loading of radionuclides and small‐molecule chemotherapeutic drugs as nanotheranostic platforms using nanozymes holds tremendous potential for imaging‐guided synergistic therapy. This study presents such nanotheranostic platform ( 177 Lu‐MFeCu@Tan) via co‐assembling 177 Lu radionuclide and tanshinone (Tan) into Fe/Cu dual‐metal nanozyme (MFeCu). This platform simultaneously enables single‐photon emission computed tomography (SPECT) imaging and a quadruple‐synergistic tumor therapy approach, including internal radioisotope therapy (RIT), catalysis therapy, chemotherapy, and MFeCu‐mediated ferroptosis and cuproptosis therapy. In this platform, the MFeCu can catalyze excessive intracellular hydrogen peroxide (H 2 O 2 ) to generate radical oxygen species (ROS) and deplete glutathione (GSH). The excess of H 2 O 2 and GSH are main factors for radioresistance and chemoresistance, reducing them can enhance chemotherapy and RIT. The generated ROS and depleted GSH further induce mitochondrial dysfunction and promote the aggregation of lipoylated dihydrolipoamide S‐acetyltransferase and lipid peroxidation, causing the enhance of ferroptosis and cuproptosis. The in vitro and in vivo results demonstrate that this quadruple‐synergistic approach shows significant therapeutic efficacy to complete tumor eradication and reduced recurrence in vivo. In conclusion, this work presents a promising strategy for designing SPECT imaging‐guided quadruple‐synergistic therapy and highlights the feasibility of developing a self‐assembled radionuclide and small molecule chemotherapy drugs nanotherapeutic platform for combined treatment of cancer.
Cuproptosis, ferroptosis and PANoptosis in tumor immune microenvironment remodeling and immunotherapy: culprits or new hope
Authors: Xiaojie Zhang, Bufu Tang, Jinhua Luo, Yang Yang, Qiaoyou Weng, Shiji Fang, Zhongwei Zhao, Jianfei Tu, Minjiang Chen, Jiansong Ji
Journal: Molecular Cancer (2024)

Normal life requires cell division to produce new cells, but cell death is necessary to maintain balance. Dysregulation of cell death can lead to the survival and proliferation of abnormal cells, promoting tumor development. Unlike apoptosis, necrosis, and autophagy, the newly recognized forms of regulated cell death (RCD) cuproptosis, ferroptosis, and PANoptosis provide novel therapeutic strategies for tumor treatment. Increasing research indicates that the death of tumor and immune cells mediated by these newly discovered forms of cell death can regulate the tumor microenvironment (TME) and influence the effectiveness of tumor immunotherapy. This review primarily elucidates the molecular mechanisms of cuproptosis, ferroptosis, and PANoptosis and their complex effects on tumor cells and the TME. This review also summarizes the exploration of nanoparticle applications in tumor therapy based on in vivo and in vitro evidence derived from the induction or inhibition of these new RCD pathways.
Mitochondrial‐Targeting Mesoporous Polydopamine Nanoparticles for Reducing Kidney Injury Caused by Depleted Uranium
Authors: Wenrun Li, Li Shen, Shiyan Fu, Yong Li, Feng Huang, Qi Li, Qinyang Lin, Hongjia Liu, Qiuchi Wang, Liyi Chen, Huanhuan Tan, Juan Li, Yazhen Zhao, Yonghong Ran, Yuhui Hao
Journal: Advanced Healthcare Materials (2024)

Abstract Depleted uranium (DU), when accidentally released from the nuclear industry, can enter the human body and cause kidney damage, as DU induces oxidative damage and apoptosis through mitochondrial pathways and inflammatory reactions. The existing nanoparticles used to treat DU injury have low bioavailability and poor targeting. In this study, mesoporous polydopamine (MPDA), poly‐(ethylene glycol) (PEG), and triphenylphosphonium (TPP) are combined to develop a novel mitochondrion‐targeting bifunctional nanoparticle, MPDA–PEG–TPP, and confirm that it can protect the kidneys from DU. This study demonstrates the high selectivity of MPDA–PEG–TPP for uranyl in uranyl chelate assays and its promising efficiency in uranyl sequestration from the kidneys, lungs, and femurs, following immediate or delayed administration of MPDA–PEG–TPP nanoparticles. In vitro assays confirm its efficiency in removing reactive oxygen species and targeting the mitochondria. In addition, in vitro and in vivo assays confirm that MPDA–PEG–TPP can reduce mitochondrial dysfunction and ameliorate kidney injury. These results suggest that MPDA–PEG–TPP is a valuable agent for ameliorating the DU‐induced kidney injury.
Polymer‐ and Lipid‐Based Nanostructures Serving Wound Healing Applications: A Review
Authors: Fatma N. Cetin, Arn Mignon, Sandra Van Vlierberghe, Kristyna Kolouchova
Journal: Advanced Healthcare Materials (2024)

Abstract Management of hard‐to‐heal wounds often requires specialized care that surpasses the capabilities of conventional treatments. Even the most advanced commercial products lack the functionality to meet the needs of hard‐to‐heal wounds, especially those complicated by active infection, extreme bleeding, and chronic inflammation. The review explores how supramolecular nanovesicles and nanoparticles—such as dendrimers, micelles, polymersomes, and lipid‐based nanocarriers—can be key to introducing advanced wound healing and monitoring properties to address the complex needs of hard‐to‐heal wounds. Their potential to enable advanced functions essential for next‐generation wound healing products—such as hemostatic functions, transdermal penetration, macrophage polarization, targeted delivery, and controlled release of active pharmaceutical ingredients (antibiotics, gaseous products, anti‐inflammatory drugs, growth factors)—is discussed via an extensive overview of the recent reports. These studies highlight that the integration of supramolecular systems in wound care is crucial for advancing toward a new generation of wound healing products and addressing significant gaps in current wound management practices. Current strategies and potential improvements regarding personalized therapies, transdermal delivery, and the promising critically evaluated but underexplored polymer‐based nanovesicles, including polymersomes and proteinosomes, for wound healing.
Clinical advances and challenges in targeting FGF/FGFR signaling in lung cancer
Authors: Mei Peng, Jun Deng, Xiangping Li
Journal: Molecular Cancer (2024)

Fibroblast growth factors (FGFs) and their receptors regulate numerous cellular processes, such as metabolism and signal transduction, but can also drive tumorigenesis. Specifically, in lung cancer, the overexpression of FGFs, as well as the amplification, mutation and fusion of FGFR genes, are closely linked to the initiation, progression and resistance of the disease, suggesting that targeting FGF/FGFR is an attractive therapeutic strategy for lung cancer treatment. Nintedanib, a multitarget tyrosine kinase inhibitor (TKI) used in combination with docetaxel, has shown some success as a second-line therapy for lung cancer. However, clinical trials evaluating other FGFR inhibitors have yielded mixed results, indicating substantial complexity in targeting aberrant FGF/FGFR signaling. In this review, we describe the aberrations in FGF/FGFR signaling in lung cancer and summarize the clinical efficacy of FGFR inhibitors, such as multitarget TKIs, selective FGFR-TKIs and biological agents. We also discuss various challenges associated with FGFR targeting in lung cancer, including precision patient selection, toxicity and resistance. Finally, we provide perspectives on future directions, namely, developing novel FGFR-targeting drugs, such as FGFR degraders and more specific FGFR-TKIs, adopting combination therapy and targeting FGFs.
Production, Characterization, and Application of Hydrophobin‐Based IR780 Nanoparticles for Targeted Photothermal Cancer Therapy and Advanced Near‐Infrared Imaging
Authors: Jiyuan Yang, Wenjun Wang, Siyuan Huang, Dingyi Guo, Long Yu, Wanjin Qiao, Xu Zhang, Zhiqiang Han, Bo Song, Xiaoting Xu, Zhenzhou Wu, Jonathan S. Dordick, Fuming Zhang, Haijin Xu, Mingqiang Qiao
Journal: Advanced Healthcare Materials (2024)

Abstract As a promising approach for breast cancer treatment, photothermal therapy (PTT) features high spatial selectivity, noninvasiveness, and minimal drug resistance. IR780 (a near‐infrared fluorescent dye) serves as an effective photosensitizer in PTT cancer therapy. However, the clinical application of IR780 in PTT has been hindered by its poor water solubility and unstable photostability. In this study, a genetically engineered dual‐functional fusion protein tLyP‐1‐MGF6 is successfully constructed and expressed, which presents a novel use of hydrophobin MGF6 for its amphiphilicity combined with the tumor‐penetrating peptide tLyP‐1 to create an innovative carrier for IR780. These results show this fusion protein serving as a biodegradable and biocompatible carrier, significantly improves the water solubility of IR780 when formulated into nanoparticles. These studies demonstrate that the IR780@tLyP‐1‐MGF6 nanoparticles significantly enhance tumor targeting and photothermal therapeutic efficacy in comparison with control in vitro and in vivo. These advancements highlight the potential of the unique combination hydrophobin‐based IR780 delivery system as a multifunctional nanoplatform for integrated imaging and targeted photothermal treatment of breast cancer.
Induction of intercrypt goblet cells upon bacterial infection: a promising therapeutic target to restore the mucosal barrier
Authors: Renaud Léonard, Ewa Pasquereau-Kotula, Edwige Madec, Benjamin Marsac, Adriana Mihalache, Laurence du Merle, Jordan Denis, Corentin Spriet, Philippe Sansonetti, Shaynoor Dramsi, Catherine Robbe Masselot
Journal: Gut Microbes (2024)

Intestinal mucins play a crucial role in the mucosal barrier, serving as the body's initial defense against microorganisms. However, how the host regulates the secretion and glycosylation of these mucins in response to bacterial invasion remains unclear. Our study demonstrates that when exposed to Streptococcus gallolyticus (SGG), a gut pathobiont, the host mucosa promptly adjusts the behavior of specialized goblet cells (GCs) located in the middle of the crypts. A subset of these cells undergoes a remodeling, becoming intercrypt goblet cells (icGCs), which do not detach from the surface but instead migrate along intercrypt spaces while secreting a mucus impermeable to bacterial pathogens. Significantly, a non-piliated SGG mutant unable to bind to mucus fails to induce icGCs, allowing its translocation through the mucosa and submucosa. Interestingly, a closely related nonpathogenic bacterium, SGM, able to bind to mucus, also triggers the differentiation of GCs into icGCs. This discovery opens new avenues for treating patients with a "leaky gut" as observed in intestinal diseases such as inflammatory bowel diseases and metabolic disorders, but also patients with a history of repeated antibiotic use. Utilizing mucus-adherent probiotics to induce icGCs represents a promising strategy for reinforcing the mucosal barrier.
High‐grade B‐cell lymphoma not otherwise specified, with diffuse large B‐cell lymphoma gene expression signatures: Genomic analysis and potential therapeutics
Authors: Waseem Lone, Alyssa Bouska, Tyler A. Herek, Catalina Amador, Joo Song, Alexander M. Xu, Dylan Jochum, Issa Ismail Issa, Dennis D. Weisenburger, Xuan Zhang, Sharath Kumar Bhagavathi, Tayla B. Heavican‐Foral, Sunandini Sharma, Ab Rauf Shah, Abdul Rouf Mir, Aisha Ahmad Alkhinji, Dalia El‐Gamal, Bhavana J. Dave, Keenan Hartert, Jiayu Yu, Mallick Saumyaranjan, Timothy C. Greiner, Julie Vose, Timothy W. McKeithan, Kai Fu, Michael Green, Chengfeng Bi, Akil Merchant, Wing C. Chan, Javeed Iqbal
Journal: American Journal of Hematology (2024)

Abstract High‐grade B‐cell lymphoma not otherwise specified (HGBCL, NOS) has overlapping morphological and genetic features with diffuse large B‐cell lymphoma (DLBCL) and Burkitt lymphoma (BL), leading to uncertainty in its diagnosis and clinical management. Using functional genomic approaches, we previously characterized HGBCL and NOS, that demonstrate gene expression profiling (GEP), and genetic signatures similar to BL. Herein, we characterize distinct HGBCL, NOS, cohort ( n = 55) in adults ( n = 45) and in children ( n = 10), and compared the GEP, genomic DNA copy number (CN), and mutational spectrum with de novo DLBCL ( n = 85) and BL ( n = 52). This subgroup, representing ~60% of HGBCL, NOS, lack gene‐expression signature of BL and double hit/dark zone lymphoma, but express DLBCL like signatures and are characterized by either GCB‐ or ABC‐like mRNA signatures and exhibit higher genomic complexity, similar to de novo DLBCL, and show alteration in genes regulating B‐cell activation ( CD79B , MYD88 , PRDM1 , TBLIXR1 , CARD11 ), epigenome ( KMT2D , TET2 ) and cell cycle transition ( TP53 , ASPM ). However, recurrent mutations in genes often mutated in BL (DDX3X, GNA13, CCND3), but rare in DLBCL, are also present in HGBCL‐NOS, highlighting genetic heterogeneity. Consistent with mutation spectrum, frequent genomic CN alterations in genes regulating B‐cell activation (del‐ PRDM1 , gain‐ BCL6 , ‐ REL , ‐ STAT3 ) and cell cycle regulators (del‐ TP53 , del‐ CDKN2A , del‐ RB1 , gain‐ CCND3 ) were observed. Pediatric cases showed GCB‐DLBCL‐like mRNA signatures, but also featured hallmark mutations of pediatric BL. Frequent oncogenic PIM1 mutations were present in adult HGBCL, NOS. In vitro analyses with pharmacologic or genetic inhibition of PIM1 expression triggered B‐cell activation and NF‐κB‐induced apoptosis, suggesting that PIM1 is a rational therapeutic target.
Poly(vinyl alcohol) potentiating an inert d-amino acid-based drug for boron neutron capture therapy
Authors: Kakeru Konarita, Kaito Kanamori, Minoru Suzuki, Daiki Tokura, Shota Tanaka, Yuto Honda, Nobuhiro Nishiyama, Takahiro Nomoto
Journal: Journal of Controlled Release (2024)

Since the discovery of d-amino acids, they have been considered inactive and have not been used as potent drugs. Here, we report that simple mixing with poly(vinyl alcohol) (PVA) unleashed latent potentials of d-amino acids in boron neutron capture therapy (BNCT). PVA formed boronate esters with seemingly useless boronated d-amino acids and induced tumor-associated amino acid transporter-superselective internalization and prolonged intracellular retention, accomplishing complete cure of tumors. The superselective internalization was achieved by switching the internalization pathway from ineffective pass through the transporter to the transporter-mediated endocytosis. The acidic environment in the endo-/lysosome dissociated the boronate esters and elicited the stealthiness of the drugs, preventing their externalization and prolonging intracellular retention time. In a subcutaneous tumor model, this system accomplished surprisingly high tumor-selective accumulation that could not be achieved by conventional approaches and induced drastic BNCT effects. PVA may be a unique material to unlock potentials of seemingly inert molecules.