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Protein & Cell Apr 2024Colorectal cancer (CRC) is a highly heterogeneous cancer and exploring novel therapeutic options is a pressing issue that needs to be addressed. Here, we established...
Colorectal cancer (CRC) is a highly heterogeneous cancer and exploring novel therapeutic options is a pressing issue that needs to be addressed. Here, we established human CRC tumor-derived organoids that well represent both morphological and molecular heterogeneities of original tumors. To efficiently identify repurposed drugs for CRC, we developed a robust organoid-based drug screening system. By combining the repurposed drug library and computation-based drug prediction, 335 drugs were tested and 34 drugs with anti-CRC effects were identified. More importantly, we conducted a detailed transcriptome analysis of drug responses and divided the drug response signatures into five representative patterns: differentiation induction, growth inhibition, metabolism inhibition, immune response promotion, and cell cycle inhibition. The anticancer activities of drug candidates were further validated in the established patient-derived organoids-based xenograft (PDOX) system in vivo. We found that fedratinib, trametinib, and bortezomib exhibited effective anticancer effects. Furthermore, the concordance and discordance of drug response signatures between organoids in vitro and pairwise PDOX in vivo were evaluated. Our study offers an innovative approach for drug discovery, and the representative transcriptome features of drug responses provide valuable resources for developing novel clinical treatments for CRC.
Topics: Humans; Colorectal Neoplasms; Drug Evaluation, Preclinical; Drug Repositioning; Early Detection of Cancer; Organoids
PubMed: 37345888
DOI: 10.1093/procel/pwad038 -
Cell Aug 2023The properties of dorsal root ganglia (DRG) neurons that innervate the distal colon are poorly defined, hindering our understanding of their roles in normal physiology...
The properties of dorsal root ganglia (DRG) neurons that innervate the distal colon are poorly defined, hindering our understanding of their roles in normal physiology and gastrointestinal (GI) disease. Here, we report genetically defined subsets of colon-innervating DRG neurons with diverse morphologic and physiologic properties. Four colon-innervating DRG neuron populations are mechanosensitive and exhibit distinct force thresholds to colon distension. The highest threshold population, selectively labeled using Bmpr1b genetic tools, is necessary and sufficient for behavioral responses to high colon distension, which is partly mediated by the mechanosensory ion channel Piezo2. This Aδ-HTMR population mediates behavioral over-reactivity to colon distension caused by inflammation in a model of inflammatory bowel disease. Thus, like cutaneous DRG mechanoreceptor populations, colon-innervating mechanoreceptors exhibit distinct anatomical and physiological properties and tile force threshold space, and genetically defined colon-innervating HTMRs mediate pathophysiological responses to colon distension, revealing a target population for therapeutic intervention.
Topics: Ganglia, Spinal; Mechanoreceptors; Colon; Neurons; Skin
PubMed: 37541195
DOI: 10.1016/j.cell.2023.07.007 -
Graefe's Archive For Clinical and... Feb 2024This study aimed to compare functional and morphologic changes in the loading phase between patients with treatment-naïve macular neovascularization (MNV) due to...
PURPOSE
This study aimed to compare functional and morphologic changes in the loading phase between patients with treatment-naïve macular neovascularization (MNV) due to neovascular age-related macular degeneration (nAMD) treated with either intravitreal brolucizumab (IVBr) or intravitreal faricimab (IVF) injections in a clinical setting.
METHODS
We retrospectively studied 92 consecutive eyes of 90 patients with neovascular nAMD who were scheduled to receive IVBr (42 eyes of 41 patients) or IVF (50 eyes of 49 patients) injections between October 2021 and December 2022. All patients received three consecutive monthly injections of 6.0 mg/0.05 mL brolucizumab or 6.0 mg/0.05 mL faricimab. The best-corrected visual acuity (BCVA), central foveal thickness (CFT), and central choroidal thickness (CCT) at baseline and 1, 2, and 4 months after the initial treatment were measured and compared between the groups.
RESULTS
Thirty-seven eyes in IVBr group and forty-seven eyes in IVF group who finished treatments in the loading phase were assessed at the follow-up examination. The BCVA, CFT, and CCT changed significantly after loading phase in both groups (P < 0.05 for both comparisons). The IVBr group had more rapid improvement of the BCVA (P = 0.037) at 1 month than the IVF group, but there was no difference at 4 months (P = 0.367). The CFT and CCT decreases tended to be greater in the IVBr group than in the IVF group throughout the follow-up period. Of the five eyes excluded from the IVBr group, one eye (2.4%) each had intraocular inflammation (IOI) and was a non-responder, and two eyes (4.8%) had retinal pigment epithelial tears after treatment. Of the three eyes excluded from the IVF group, two eyes (4.0%) did not respond to the treatment.
CONCLUSIONS
Both IVBr and IVF injections were well-tolerated and improved the VA in treatment-naïve patients with MNV due to nAMD after a loading phase, although IVBr caused a trend toward faster visual improvements in the BCVA. The IVBr group also had greater reductions of the CFT and CCT than the IVF group. However, the potential for adverse events and no response to treatment with each drug are considerations.
Topics: Humans; Retrospective Studies; Tomography, Optical Coherence; Retinal Perforations; Intravitreal Injections; Macular Degeneration; Angiogenesis Inhibitors; Wet Macular Degeneration; Receptors, Vascular Endothelial Growth Factor; Antibodies, Bispecific; Antibodies, Monoclonal, Humanized
PubMed: 37750953
DOI: 10.1007/s00417-023-06241-8 -
Cell Mar 2024Dorsal root ganglia (DRG) somatosensory neurons detect mechanical, thermal, and chemical stimuli acting on the body. Achieving a holistic view of how different DRG...
Dorsal root ganglia (DRG) somatosensory neurons detect mechanical, thermal, and chemical stimuli acting on the body. Achieving a holistic view of how different DRG neuron subtypes relay neural signals from the periphery to the CNS has been challenging with existing tools. Here, we develop and curate a mouse genetic toolkit that allows for interrogating the properties and functions of distinct cutaneous targeting DRG neuron subtypes. These tools have enabled a broad morphological analysis, which revealed distinct cutaneous axon arborization areas and branching patterns of the transcriptionally distinct DRG neuron subtypes. Moreover, in vivo physiological analysis revealed that each subtype has a distinct threshold and range of responses to mechanical and/or thermal stimuli. These findings support a model in which morphologically and physiologically distinct cutaneous DRG sensory neuron subtypes tile mechanical and thermal stimulus space to collectively encode a wide range of natural stimuli.
Topics: Animals; Mice; Ganglia, Spinal; Sensory Receptor Cells; Single-Cell Gene Expression Analysis; Skin
PubMed: 38442711
DOI: 10.1016/j.cell.2024.02.006 -
Nature Communications Oct 2023Digital pathology allows computerized analysis of tumor ecosystem using whole slide images (WSIs). Here, we present single-cell morphological and topological profiling...
Digital pathology allows computerized analysis of tumor ecosystem using whole slide images (WSIs). Here, we present single-cell morphological and topological profiling (sc-MTOP) to characterize tumor ecosystem by extracting the features of nuclear morphology and intercellular spatial relationship for individual cells. We construct a single-cell atlas comprising 410 million cells from 637 breast cancer WSIs and dissect the phenotypic diversity within tumor, inflammatory and stroma cells respectively. Spatially-resolved analysis identifies recurrent micro-ecological modules representing locoregional multicellular structures and reveals four breast cancer ecotypes correlating with distinct molecular features and patient prognosis. Further analysis with multiomics data uncovers clinically relevant ecosystem features. High abundance of locally-aggregated inflammatory cells indicates immune-activated tumor microenvironment and favorable immunotherapy response in triple-negative breast cancers. Morphological intratumor heterogeneity of tumor nuclei correlates with cell cycle pathway activation and CDK inhibitors responsiveness in hormone receptor-positive cases. sc-MTOP enables using WSIs to characterize tumor ecosystems at the single-cell level.
Topics: Humans; Female; Breast Neoplasms; Ecosystem; Triple Negative Breast Neoplasms; Tumor Microenvironment
PubMed: 37880211
DOI: 10.1038/s41467-023-42504-y -
Frontiers in Endocrinology 2023The human endometrium is only receptive to an implanting blastocyst in the mid-secretory phase of each menstrual cycle. Such time-dependent alterations in function... (Review)
Review
The human endometrium is only receptive to an implanting blastocyst in the mid-secretory phase of each menstrual cycle. Such time-dependent alterations in function require intricate interplay of various factors, largely coordinated by estrogen and progesterone. Abnormal endometrial receptivity is thought to contribute to two-thirds of the implantation failure in humans and therefore significantly hindering IVF success. Despite the incontrovertible importance of endometrial receptivity in implantation, the precise mechanisms involved in the regulation of endometrial receptivity remain poorly defined. This is mainly due to a lack of proper models that recapitulate the environment of the receptive human endometrium. Organoids were recently established from human endometrium with promising features to better mimic the receptive phase. Endometrial organoids show long-term expandability and the capability to preserve the structural and functional characteristics of the endometrial tissue of origin. This three-dimensional model maintains a good responsiveness to steroid hormones and replicates key morphological features of the receptive endometrium , including pinopodes and pseudostratified epithelium. Here, we review the current findings of endometrial organoid studies that have been focused on investigating endometrial receptivity and place an emphasis on methods to further refine and improve this model.
Topics: Female; Humans; Endometrium; Menstrual Cycle; Blastocyst; Embryo Implantation; Organoids
PubMed: 37693361
DOI: 10.3389/fendo.2023.1158515 -
Scientific Reports Apr 2024Mitochondria, the powerhouse and the vital signaling hub of the cell, participate in a variety of biological processes, such as apoptosis, redox responses, cell...
Mitochondria, the powerhouse and the vital signaling hub of the cell, participate in a variety of biological processes, such as apoptosis, redox responses, cell senescence, autophagy, and iron homeostasis. Mitochondria form a mostly tubular network, made up of an outer and a cristeae-forming inner membrane. The network undergoes dynamic fusion and fission that change its morphological structure according to the functional needs. Approximately 1500 mitochondrial proteins encoded by nuclear genome plus over 10 proteins encoded by mitochondrial DNA are folded and assembled in the mitochondria under a high-fidelity control system. These proteins are involved in oxidative phosphorylation, metabolism, network and cristae dynamics, mitophagy, import machinery, ion channels, and mitochondrial DNA maintenance. This Collection gathers original research that advances our understanding of the monitoring techniques and pathophysiological significance of mitochondrial dynamics in health and disease.
Topics: Mitochondrial Dynamics; Humans; Mitochondria; Animals
PubMed: 38688939
DOI: 10.1038/s41598-024-59998-1 -
Journal of Nuclear Medicine : Official... Sep 2023Recent innovative strategies have dramatically redefined the therapeutic landscape for treating multiple myeloma patients. In particular, the development and application...
Recent innovative strategies have dramatically redefined the therapeutic landscape for treating multiple myeloma patients. In particular, the development and application of immunotherapy and high-dose therapy have demonstrated high response rates and have prolonged remission duration. Over the past decade, new morphologic or hybrid imaging techniques have gradually replaced conventional skeletal surveys. PET/CT using F-FDG is a powerful imaging tool for the workup at diagnosis and for therapeutic evaluation allowing medullary and extramedullary assessment. The independent negative prognostic value for progression-free and overall survival derived from baseline PET-derived parameters such as the presence of extramedullary disease or paramedullary disease, as well as the number of focal bone lesions and SUV, has been reported in several large prospective studies. During therapeutic evaluation, F-FDG PET/CT is considered the reference imaging technique because it can be performed much earlier than MRI, which lacks specificity. Persistence of significant abnormal F-FDG uptake after therapy is an independent negative prognostic factor, and F-FDG PET/CT and medullary flow cytometry are complementary tools for detecting minimal residual disease before maintenance therapy. The definition of a PET metabolic complete response has recently been standardized and the interpretation criteria harmonized. The development of advanced PET analysis and radiomics using machine learning, as well as hybrid imaging with PET/MRI, offers new perspectives for multiple myeloma imaging. Most recently, innovative radiopharmaceuticals such as C-X-C chemokine receptor type 4-targeted small molecules and anti-CD38 radiolabeled antibodies have shown promising results for tumor phenotype imaging and as potential theranostics.
Topics: Humans; Multiple Myeloma; Fluorodeoxyglucose F18; Positron Emission Tomography Computed Tomography; Prospective Studies; Immunotherapy
PubMed: 37591548
DOI: 10.2967/jnumed.122.264972 -
Theranostics 2023Tumor vasculature plays a critical role in the progression and metastasis of tumors, antitumor immunity, drug delivery, and resistance to therapies. The morphological... (Review)
Review
Tumor vasculature plays a critical role in the progression and metastasis of tumors, antitumor immunity, drug delivery, and resistance to therapies. The morphological and functional changes of tumor vasculature in response to therapy take place in a spatiotemporal-dependent manner, which can be predictive of treatment outcomes. Dynamic monitoring of intratumor vasculature contributes to an improved understanding of the mechanisms of action of specific therapies or reasons for treatment failure, leading to therapy optimization. There is a rich history of methods used to image the vasculature. This review describes recent advances in imaging technologies to visualize the tumor vasculature, with a focus on enhanced intravital imaging techniques and tumor window models. We summarize new insights on spatial-temporal vascular responses to various therapies, including changes in vascular perfusion and permeability and immune-vascular crosstalk, obtained from intravital imaging. Finally, we briefly discuss the clinical applications of intravital imaging techniques.
Topics: Humans; Tumor Microenvironment; Neoplasms; Intravital Microscopy; Treatment Outcome
PubMed: 37908739
DOI: 10.7150/thno.84947 -
The Journal of Experimental Medicine Jan 2024Fibroblastic reticular cells (FRCs) are specialized fibroblasts of secondary lymphoid organs that provide the structural foundation of the tissue. Moreover, FRCs guide... (Review)
Review
Fibroblastic reticular cells (FRCs) are specialized fibroblasts of secondary lymphoid organs that provide the structural foundation of the tissue. Moreover, FRCs guide immune cells to dedicated microenvironmental niches where they provide lymphocytes and myeloid cells with homeostatic growth and differentiation factors. Inflammatory processes, including infection with pathogens, induce rapid morphological and functional adaptations that are critical for the priming and regulation of protective immune responses. However, adverse FRC reprogramming can promote immunopathological tissue damage during infection and autoimmune conditions and subvert antitumor immune responses. Here, we review recent findings on molecular pathways that regulate FRC-immune cell crosstalk in specialized niches during the generation of protective immune responses in the course of pathogen encounters. In addition, we discuss how FRCs integrate immune cell-derived signals to ensure protective immunity during infection and how therapies for inflammatory diseases and cancer can be developed through improved understanding of FRC-immune cell interactions.
Topics: Lymphocytes; Fibroblasts; Lymph Nodes
PubMed: 38038708
DOI: 10.1084/jem.20221220