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We report the development of a head-mounted photoacoustic fiberscope for cerebral imaging in a freely behaving mouse. The 4.5-gram imaging probe has a 9-µm lateral resolution and 0.2-Hz frame rate over a 1.2-mm wide area. The probe can continuously monitor cerebral oxygenation and hemodynamic responses at single-vessel resolution, showing significantly different cerebrovascular responses to external stimuli under anesthesia and in the freely moving state. For example, when subjected to high-concentration CO2 respiration, enhanced oxygenation to compensate for hypercapnia can be visualized due to cerebral regulation in the freely moving state. Comparative studies exhibit significantly weakened compensation capabilities in obese rodents. This new imaging modality can be used for investigating both normal and pathological cerebrovascular functions and shows great promise for studying cerebral activity, disorders and their treatments.

Microcirculation monitoring is crucial for evaluating cardiovascular health and detecting organ dysfunction early, but existing bedside imaging techniques often cannot provide sufficient resolution and depth for dynamic assessment during natural physiological activities. Here, we present MOBILE (Miniaturized Omnidirectional Broadband Photoacoustic Imaging System for Living Entities), a photoacoustic imaging system that allows unrestricted microcirculatory monitoring with 40 µm resolution and penetration depth of 10 mm, allowing stratified visualization of dynamic vascular responses. This platform features an ultracompact fibre-optic sensor capable of omnidirectional ultrasound-based detection across a large bandwidth (0.3–80 MHz). The compact design of the system facilitates point-of-care monitoring through seamless integration with portable devices or existing clinical systems. Through a comprehensive evaluation of the patient’s haemodynamic parameters, MOBILE reveals distinct dynamic responses of vessels at different tissue depths, from superficial microvessels to deep subcutaneous vessels, capturing vessel-specific changes in diameter, haemoglobin concentration, and tissue oxygenation during numerous physiological challenges. This platform offers possibilities for understanding microcirculatory responses and improving critical care management through high-resolution vessel monitoring. The authors developed MOBILE, a compact photoacoustic imaging system for non-invasive hemodynamic monitoring in motion. It reveals how microcirculation adapt during exercise, offering a dynamic window into cardiovascular health.

CD16a triggers antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis by natural killer (NK) cells and macrophages in anti-tumor immunity. However, CD16a undergoes cleavage by ADAM17 that dampens its anti-tumor immunity. We here develop a monoclonal antibody (F9H4) that binds to CD16a and inhibits its cleavage. F9H4 retains CD16a on the surface of NK cells and macrophages, without triggering or blocking CD16a. F9H4 also binds to and inhibits shedding of CD16b by neutrophils, and inhibits CD16a/b shedding by leukocytes in tumor samples from lung cancer patients. F9H4 promotes ADCC against lung cancer cells that are opsonized by cetuximab, an epidermal growth factor receptor antibody that engages CD16a. F9H4 synergizes with cetuximab to inhibit human lung adenocarcinoma development in immunodeficient mice reconstituted with human NK cells. F9H4 combining with cetuximab also inhibits murine lung carcinoma growth in Fc gamma receptor-humanized mice, and such effect is mediated by NK cells and macrophages. The efficacy of F9H4+cetuximab in lung cancer models is the proof-of-concept for this new approach that promotes anti-tumor functions of Fc-enabled antibodies. CD16a triggers antibody-dependent cellular cytotoxicity but CD16a shedding dampens its anti-tumor activity. Here the authors develop a monoclonal antibody (F9H4) that prevents CD16a shedding, which synergizes with a tumor cell opsonizing antibody (cetuximab) to elicit natural killer cell-driven immunity.

Objectives/Goals: The Clinical Research Education in Genome Science (CREiGS) program was developed to address the need for faculty and trainees conducting biomedical research to gain foundational training in genome science and accelerate the clinical adoption of genomic medicine. CREiGS, funded by NHGRI, offers comprehensive training in genomic analysis and statistical computing. Methods/Study Population: CREiGS targets a diverse pool of medical/doctoral students, postdocs, and faculty from academic institutions nationwide. The hybrid program included an 11-week online phase and a 3-day in-person phase, focusing on genomic science, statistical analysis and R programming, rigor and reproducibility, and engaging diverse populations in genomics research. Advanced special topics lectures included: decision analysis for genomics research, bioethical engagement of indigenous communities in genomics research, elucidating gene networks for advancing human health, etc. Strategies for recruiting diverse participants and ensuring an inclusive learning environment were informed by the Diversity Recruitment External Advisory Board. Participants’ skills were evaluated via pre- and post-course surveys. Results/Anticipated Results: Of 187 participants over 5 cohorts, 68.4% were female and 47.0% from underrepresented groups. The cohort spanned career stages, with 35.3% students, 34.2% postdocs, and 30.4% faculty, most of whom were at the junior level. Competency evaluations showed improvements in all core competencies of the course: (1) independently carrying out small-scale research improvements, (2) confidence collaborating with statisticians, bioinformaticians, and other genome science experts, (3) applying appropriate statistical methods for the analysis of genetics and genomics data, (4) accurately interpreting findings from genome research studies, (5) critiquing the internal/external validity of genome research studies, and (6) effectively engaging diverse populations and community stakeholders. Discussion/Significance of Impact: CREiGS successfully provided inclusive, high-quality, genomic and statistical training, to diverse scientists enhancing their research capacity and methodologic competency. Findings from longer term evaluations examining the contribution of CREiGS to participants’ genome science-related scholarly productivity are forthcoming.

A variety of programmed cell death types have been shown to participate in the loss of smooth muscle cells (SMCs) during the development of aortic dissection (AD), but it is still largely unclear whether ferroptosis is involved in the development of AD. In the present study, we found that the expression of key ferroptosis regulatory proteins, solute carrier family 7 member 11 (SLC7A11), ferroptosis suppressor protein 1 (FSP1) and glutathione peroxidase 4 (GPX4) were downregulated in aortas of Stanford type A AD (TAAD) patients, and liproxstatin-1, a specific inhibitor of ferroptosis, obviously abolished the β-aminopropionitrile (BAPN)-induced development and rupture of AD in mice. Furthermore, the expression of methyltransferase-like 3 (METTL3), a major methyltransferase of RNA m6A, was remarkably upregulated in the aortas of TAAD patients, and the protein levels of METTL3 were negatively correlated with SLC7A11 and FSP1 levels in human aortas. Overexpression of METTL3 in human aortic SMCs (HASMCs) inhibited, while METTL3 knockdown promoted SLC7A11 and FSP1 expression. More importantly, overexpression of METTL3 facilitated imidazole ketone erastin- and cystine deprivation-induced ferroptosis, while knockdown of METTL3 repressed ferroptosis of HASMCs. Overexpression of either SLC7A11 or FSP1 largely abrogated the effect of METTL3 on HASMC ferroptosis. Therefore, we have revealed that ferroptosis is a critical cause of AD in both humans and mice and that METTL3 promotes ferroptosis of HASMCs by inhibiting the expression of SLC7A11 and FSP1. Thus, targeting ferroptosis or m6A RNA methylation is a potential novel strategy for the treatment of AD.A variety of programmed cell death types have been shown to participate in the loss of smooth muscle cells (SMCs) during the development of aortic dissection (AD), but it is still largely unclear whether ferroptosis is involved in the development of AD. In the present study, we found that the expression of key ferroptosis regulatory proteins, solute carrier family 7 member 11 (SLC7A11), ferroptosis suppressor protein 1 (FSP1) and glutathione peroxidase 4 (GPX4) were downregulated in aortas of Stanford type A AD (TAAD) patients, and liproxstatin-1, a specific inhibitor of ferroptosis, obviously abolished the β-aminopropionitrile (BAPN)-induced development and rupture of AD in mice. Furthermore, the expression of methyltransferase-like 3 (METTL3), a major methyltransferase of RNA m6A, was remarkably upregulated in the aortas of TAAD patients, and the protein levels of METTL3 were negatively correlated with SLC7A11 and FSP1 levels in human aortas. Overexpression of METTL3 in human aortic SMCs (HASMCs) inhibited, while METTL3 knockdown promoted SLC7A11 and FSP1 expression. More importantly, overexpression of METTL3 facilitated imidazole ketone erastin- and cystine deprivation-induced ferroptosis, while knockdown of METTL3 repressed ferroptosis of HASMCs. Overexpression of either SLC7A11 or FSP1 largely abrogated the effect of METTL3 on HASMC ferroptosis. Therefore, we have revealed that ferroptosis is a critical cause of AD in both humans and mice and that METTL3 promotes ferroptosis of HASMCs by inhibiting the expression of SLC7A11 and FSP1. Thus, targeting ferroptosis or m6A RNA methylation is a potential novel strategy for the treatment of AD.

Acute myeloid leukemia (AML) is a heterogeneous clonal malignancy and challenging to treat, due to treatment resistance development. Our study seeks an immunotherapeutic approach against AML, by targeting malignant cells in a manner that is independent of neo-antigens. We focus on Major histocompatibility complex class I polypeptide-related sequence A and B (MICA/MICB), which are stress-induced proteins expressed by AML cells but shed to enable immune evasion. Our lab previous results shows that an antibody, 7C6-hIgG1, initiates antibody-dependent cellular phagocytosis of AML cells, and in combination with romidepsin, it enhances MICA/MICB expression. This suggests a synergistic AML treatment strategy. Here, we engineered the 7C6 antibody's Fc region to display GAALIE mutations, promoting stronger macrophage-mediated immunity. Results showed 7C6-GAALIE induces superior antibody-dependent cellular phagocytosis of AML cells in vitro and reduces AML burden in vivo.

Acute myeloid leukemia (AML) is a hematological malignancy characterized by clonal expansion of stem and myeloid progenitor cells. Immunotherapy has revolutionized the care for other cancers such as solid tumors and lymphomas, and has the potential to effectively treat AML. There has been substantial progress in the developments of immunotherapeutic approaches for AML over the last several years, including the development of antibodies that further increase the innate immunogenicity of leukemia cells by the inhibition of NKG2D ligand—particularly MICA and MICB—shedding, chimeric proteins such as IL-15 superagonist that expand natural killer (NK) cells, blockers of immunologic checkpoints such as NKG2A, and chemicals that indirectly increase expression of immune stimulatory proteins in leukemia stem cells. Furthermore, cellular therapies have been designed to enable alloreactive immunity by allogeneic NK cells or target leukemia antigens such as mutated NPM1. These immunotherapeutic approaches have demonstrated remarkable efficacies in preclinical studies and have successfully transitioned to early phase clinical trials, to establish safety and initial signal of clinical activity. Here, we briefly discuss some of the most recent and impactful developments in the AML immunotherapy field and provide our perspectives for the future directions of this exciting and new therapeutic opportunity.

Prevention of neointima formation is the key to improving long‐term outcomes after stenting or coronary artery bypass grafting. RNA N6‐methyladenosine (m6A) methylation has been reported to be involved in the development of various cardiovascular diseases, but whether it has a regulatory effect on neointima formation is unknown. Herein, we revealed that methyltransferase‐like 3 (METTL3), the major methyltransferase of m6A methylation, was downregulated during vascular smooth muscle cell (VSMC) proliferation and neointima formation. Knockdown of METTL3 facilitated, while overexpression of METTL3 suppressed the proliferation of human aortic smooth muscle cells (HASMCs) by arresting HASMCs at G2/M checkpoint and the phosphorylation of CDC2 (p‐CDC2) was inactivated by METTL3. On the other hand, the migration and synthetic phenotype of HASMCs were enhanced by METTL3 knockdown, but inhibited by METTL3 overexpression. The protein levels of matrix metalloproteinase 2 (MMP2), MMP7 and MMP9 were reduced, while the expression level of tissue inhibitor of metalloproteinase 3 was increased in HASMCs with METTL3 overexpression. Moreover, METTL3 promoted the autophagosome formation by upregulating the expression of ATG5 (autophagy‐related 5) and ATG7. Knockdown of either ATG5 or ATG7 largely reversed the regulatory effects of METTL3 overexpression on phenotypic switching of HASMCs, as evidenced by increased proliferation and migration, and predisposed to synthetic phenotype. These results indicate that METTL3 inhibits the phenotypic switching of VSMCs by positively regulating ATG5‐mediated and ATG7‐mediated autophagosome formation. Thus, enhancing the level of RNA m6A or the formation of autophagosomes is the promising strategy to delay neointima formation. The expression of methyltransferase‐like 3 (METTL3) was inhibited by proliferation inducers in vascular smooth muscle cells (VSMCs). Overexpression of METTL3 promotes autophagy‐related 5 (ATG5) and ATG7 protein expression to facilitate autophagosome formation, which subsequently inhibits VSMC proliferation, migration and switching from contractile to synthetic phenotype. Knockdown of either ATG5 or ATG7 largely reversed the inhibitory effects of METTL3 on proliferation, migration and phenotypic switching of VSMCs. These findings indicate that METTL3 may inhibit neointima formation by accelerating the formation of autophagosomes.

A consistent positive association between cigarette smoking and the human esophageal cancer has been confirmed all over the world. However, details in the association need to be more focused on and be identified. Recently, aberrantly expressed microRNAs (miRNAs) have been shown to be promising biomarkers for understanding the tumorigenesis of a wide array of human cancers, including the esophageal cancer, and the deregulation on the epithelial to mesenchymal transition (EMT) by miRNAs is involved in the tumorigenesis. In present study, we were going to identify the role of nicotine-induced miR-21 in the EMT of esophageal cells. We found that there was an overexpression of miR-21 in esophageal specimens, having an association with cigarette smoking, and the upregulation of miR-21 was also induced by nicotine in esophageal carcinoma cell line, EC9706. Moreover, the upregulated miR-21 by nicotine promoted EMT transforming growth factor beta (TGF-β) dependently. Thus, the present study reveals a novel oncogenic role of nicotine in human esophageal cancer.

Brain metastasis is thought to be related to the high mortality and poor prognosis of lung cancer. Despite significant advances in the treatment of primary lung cancer, the unique microenvironment of the brain renders current therapeutic strategies largely ineffective against brain metastasis. The lack of effective drugs for brain metastasis treatment is primarily due to the incomplete understanding of the mechanisms underlying its initiation and progression. Currently, our understanding of brain metastasis remains limited, primarily due to the absence of appropriate models that can realistically simulate the entire process of tumor cell detachment from the primary site, circulation through the bloodstream, and eventual colonization of the brain. Therefore, there is a pressing need to develop more suitable lung cancer brain metastasis models that can effectively replicate these critical stages of metastasis. Here, based on the traditional carotid artery injection model, we established a novel orthotopic mouse model by using a light-controlled hydrogel to repair the puncture site on the carotid artery, with sustained cerebral blood circulation and the capability of multiple delivery cancer cell to mimic lung cancer brain metastasis. The optimized orthotopic mouse model significantly reduced cerebral ischemia and improved cerebral oxygenation by 60% compared to the traditional orthotopic mouse model, enhancing post-operative survival rates. It also showed a reduction in pro-inflammatory cytokines and featured less inflammatory and more resting states of microglial and astrocyte cells. Furthermore, the optimized orthotopic mouse model markedly increased the success rate and absolute number of the metastatic clones in the brain. Additionally, the multiple delivery model based on the optimized orthotopic mouse model substantially augmented the tumor clone number and formation rates compared to single injection in the optimized orthotopic mouse model. This model overcomes previous limitations by maintaining cerebral circulation, providing a more accurate simulation of the continuous entry of tumor cells into cerebral circulation. It offers a robust platform for studying the interactions of cancer cells with the brain microenvironment and testing new therapeutic approaches. Graphical abstract