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Mucosal acidosis elicits a unique molecular signature in epithelia and intestinal tissue mediated by GPR31-induced CREB phosphorylation.

Metabolic changes associated with tissue inflammation result in significant extracellular acidosis (EA). Within mucosal tissues, intestinal epithelial cells (IEC) have evolved adaptive strategies to cope with EA through the up-regulation of SLC26A3 to promote pH homeostasis. We hypothesized that EA significantly alters IEC gene expression as an adaptive mechanism to counteract inflammation. Using an unbiased RNA sequencing approach, we defined the impact of EA on IEC gene expression to define molecular mechanisms by which IEC respond to EA. This approach identified a unique gene signature enri

Krüppel-like Factor 5 Regulates Stemness, Lineage Specification, and Regeneration of Intestinal Epithelial Stem Cells.

BACKGROUND & AIMS: Self-renewal and multipotent differentiation are cardinal properties of intestinal stem cells (ISCs), mediated in part by WNT and NOTCH signaling. Although these pathways are well characterized, the molecular mechanisms that control the 'stemness' of ISCs are still not well defined. Here, we investigated the role of Krüppel-like factor 5 (KLF5) in regulating ISC functions. METHODS: We performed studies in adult Lgr5EGFP-IRES-creERT2;Rosa26LSLtdTomato (Lgr5Ctrl) and Lgr5EGFP-IRES-creERT2;Klf5fl/fl;Rosa26LSLtdTomato (Lgr5ΔKlf5) mice. Mice were injected with tamoxifen to activ

Targeting Pin1 renders pancreatic cancer eradicable by synergizing with immunochemotherapy.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by notorious resistance to current therapies attributed to inherent tumor heterogeneity and highly desmoplastic and immunosuppressive tumor microenvironment (TME). Unique proline isomerase Pin1 regulates multiple cancer pathways, but its role in the TME and cancer immunotherapy is unknown. Here, we find that Pin1 is overexpressed both in cancer cells and cancer-associated fibroblasts (CAFs) and correlates with poor survival in PDAC patients. Targeting Pin1 using clinically available drugs induces complete elimination or sustained remissi

Mapping oncogenic protein interactions for precision medicine.

Normal protein-protein interactions (normPPIs) occur with high fidelity to regulate almost every physiological process. In cancer, this highly organised and precisely regulated network is disrupted, hijacked or reprogrammed resulting in oncogenic protein-protein interactions (oncoPPIs). OncoPPIs, which can result from genomic alterations, are a hallmark of many types of cancers. Recent technological advances in the field of mass spectrometry (MS)-based interactomics, structural biology and drug discovery have prompted scientists to identify and characterise oncoPPIs. Disruption of oncoPPI inte

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… was studied using mouse tumour organoids using computational PPI networks. 114 Mouse tumour organoids have also been used for functional validation of PPI inhibitors, Poloppin and Poloppin‐II, which inhibit Polo‐like kinase interactions. 115 Although patient‐derived organoids are technically challenging … TABLE 1 Human organoid biobanks with the number of tumour and normal organoids a Normal‐like, noncancer organoids that have a normal phenotype but grown from a cancer sample; brackets indicate that organoids were established but could not be propagated long‐term. …

Modeling the Bone Marrow Niche in Multiple Myeloma: From 2D Cultures to 3D Systems.

Multiple myeloma is a hematologic malignancy characterized by the clonal proliferation of plasma cells within the bone marrow. The tumor microenvironment plays a crucial role in multiple myeloma pathogenesis, progression, and drug resistance. Traditional two-dimensional cell culture models have been instrumental in multiple myeloma research. However, they fail to recapitulate the complex in vivo bone marrow microenvironment, leading to limited predictive value for clinical outcomes. Three-dimensional cell culture models emerged as more physiologically relevant systems, offering enhanced insigh

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… In recent years, there has been an improvement in the success rate of organoid establishment, alongside an expansion in the variety of organoid types. … Incorporating functional vasculature and neural elements into organoid systems also remains a major obstacle. Moreover, studies indicated that tumor-derived organoids may exhibit abnormal cell division, resulting in slower proliferation rates compared to organoids derived from healthy tissues. …

A Review on SARS-CoV-2-Induced Neuroinflammation, Neurodevelopmental Complications, and Recent Updates on the Vaccine Development.

Coronavirus disease 2019 (COVID-19) is a devastating viral infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The incidence and mortality of COVID-19 patients have been increasing at an alarming rate. The mortality is much higher in older individuals, especially the ones suffering from respiratory distress, cardiac abnormalities, renal diseases, diabetes, and hypertension. Existing evidence demonstrated that SARS-CoV-2 makes its entry into human cells through angiotensin-converting enzyme 2 (ACE-2) followed by the uptake of virions through cathepsin L or transmem

The osteogenic niche-targeted arsenic nanoparticles prevent colonization of disseminated breast tumor cells in the bone.

Up to 70% of patients with late-stage breast cancer have bone metastasis. Current treatment regimens for breast cancer bone metastasis are palliative with no therapeutic cure. Disseminated tumor cells (DTCs) colonize inside the osteogenic niches in the early stage of bone metastasis. Drug delivery into osteogenic niches to inhibit DTC colonization can prevent bone metastasis from entering its late stage and therefore cure bone metastasis. Here, we constructed a 50% DSS6 peptide conjugated nanoparticle to target the osteogenic niche. The osteogenic niche was always located at the endosteum with

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… The heterotypic organoids were grown for 4 days. The morphology and fluorescence image of organoids were captured with inverted fluorescence phase contrast microscope (Nikon). The sizes of organoids were determined by Image J software (National Institutes of Health). … Interestingly, these scattered cells were identified as 4T1-RFP cells with red fluorescence, which were not involved in the organoid formation. Meanwhile, arsenic pretreatment also shrank the sizes of heterotypic organoids ( Fig. 4 C). …

The functional imperative in high-grade glioma.

Precision oncology has emerged as a promising strategy for treating high-grade gliomas, yet its clinical impact has been disappointing, with over 300 clinical trials on targeted therapies failing to yield substantial improvements in patient outcomes. Current approaches primarily focus on static, marker-driven tumor features, which capture only a small portion of the complex biology that governs therapeutic responses. Functional precision oncology (FPO) offers a complementary approach, enhancing treatment selection in a personalized manner by dynamically testing patient-derived tumor cells agai

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… Tumor cells are isolated and processed to generate patient-derived tumor models, including organoids, tumorspheres or xenografts. … In HGG, preclinical studies have demonstrated the feasibility of co-culturing organoids with chimeric antigen receptor T cells for therapeutic testing 84 . …

Advances and Challenges in Cancer Stem Cells for Onco-Therapeutics.

Six decades have passed since the foundational recognition of the primary properties of the stem cells. Research on stem cells has since remained at the forefront of efforts to combat a spectrum of diseases, most notably cancer. Despite remarkable progress in medical science, a definitive cure for cancer has remained elusive, spurring the pursuit of diverse therapeutic strategies, among which stem cell therapy is a particularly promising avenue. Moreover, the utilization of cancer stem cells as a therapeutic source holds immense potential for addressing intractable diseases. The strategy of ta

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… However, despite their potential, there are several limitations associated with organoid research in the context of cancer. The success rates of generating organoid models vary greatly, and the conditions for organoid culture require optimization to enhance reproducibility [ 88 ]. … Therefore, organoids have significant potential in cancer research but addressing these limitations and advancing organoid technology will be crucial to unlock their full potential as reliable preclinical and clinical models for drug screening and personalized medicine. …

N-of-1 Healthcare: Challenges and Prospects for the Future of Personalized Medicine.

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… For example, a patient-derived organoid (PDO) model can utilize patient-specific stem cells to grow organoids that resemble the dynamic behavior of original organs and thus, enable personalized interventions in clinically-relevant contexts ( 20 – 22 ). How the Data Is Acquired vs. … Patient-derived organoid models help define personalized management of gastrointestinal cancer. J Br Surg. (2018) 105:e48–60. 10.1002/bjs.10726 22. Yang H, Sun L, Liu M, Mao Y. Patient-Derived Organoids: A Promising Model for Personalized Cancer Treatment. …

Advancing Medulloblastoma Treatment: Molecular Mechanisms, Drug Repurposing, and Precision Therapies.

Medulloblastomas are the most common malignant pediatric brain tumors, representing approximately 20% of the central nervous system cancers in children. These tumors are highly heterogeneous and classified into four molecular subgroups-WNT, SHH, Group 3, and Group 4-each with distinct genetic and epigenetic profiles that influence tumor behavior, therapeutic response, and patient outcomes. Advances in molecular diagnostics have improved the subclassification of medulloblastomas, yet treatment outcomes for high-risk subtypes, particularly Group 3, remain poor, with current modalities often asso

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… Organoid Models Organoids derived from patient tumors, xenografts, or induced pluripotent stem cells have emerged as powerful models for pediatric brain tumors, offering a level of biological fidelity that surpasses conventional two-dimensional cultures. … Importantly, while patient-derived organoids allow for direct study of patient-specific mutations and drug sensitivities, xenograft-derived organoids add the capacity to model tumor growth and host–tumor interactions within an in vivo context [ 63 ]. …

Exploring the promising potential of induced pluripotent stem cells in cancer research and therapy.

The advent of iPSCs has brought about a significant transformation in stem cell research, opening up promising avenues for advancing cancer treatment. The formation of cancer is a multifaceted process influenced by genetic, epigenetic, and environmental factors. iPSCs offer a distinctive platform for investigating the origin of cancer, paving the way for novel approaches to cancer treatment, drug testing, and tailored medical interventions. This review article will provide an overview of the science behind iPSCs, the current limitations and challenges in iPSC-based cancer therapy, the ethical

IL-20RB mediates tumoral response to osteoclastic niches and promotes bone metastasis of lung cancer.

Bone is a common site of metastasis in lung cancer, but the regulatory mechanism remains incompletely understood. Osteoclasts are known to play crucial roles in osteolytic bone metastasis by digesting bone matrix and indirectly enhancing tumor colonization. In this study, we found that IL receptor 20 subunit β (IL-20RB) mediated a direct tumoral response to osteoclasts. Tumoral expression of IL-20RB was associated with bone metastasis of lung cancer, and functionally, IL-20RB promoted metastatic growth of lung cancer cells in bone. Mechanistically, tumor cells induced osteoclasts to secrete th

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… Organoid culture. Cells were plated in Matrigel (BD Biosciences) and covered with organoid culture medium. A total of 500 to 1,000 cells were plated in each well of a 24-well plate; on days 7 to 14, the numbers of the organoids were analyzed. … systems Trends Mol Med 2017 23 5 393 410 10.1016/j.molmed.2017.02.007 28341301 50 Neal JT et al Organoid modeling of the tumor immune microenvironment Cell 2018 175 7 1972 1988 10.1016/j.cell.2018.11.021 30550791 PMC6656687 51 Sachs N et al Long-term expanding human airway organoids for disease modeling …

Advances in Gold Nanoparticle-Based Combined Cancer Therapy.

According to the global cancer observatory (GLOBOCAN), there are approximately 18 million new cancer cases per year worldwide. Cancer therapies are largely limited to surgery, radiotherapy, and chemotherapy. In radiotherapy and chemotherapy, the maximum tolerated dose is presently being used to treat cancer patients. The integrated development of innovative nanoparticle (NP) based approaches will be a key to address one of the main issues in both radiotherapy and chemotherapy: normal tissue toxicity. Among other inorganic NP systems, gold nanoparticle (GNP) based systems offer the means to fur

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… This can be achieved through the use of three-dimensional organoid models [ 180 ]. Organoid models have many advantages if implemented into a personalized medicine protocol. … In the future, the use of organoids to screen chemoradiotherapy protocols with GNPs may enable an accurate assessment of response and allow for tailored, personalized medical care. Figure 10 Organoid models toward personalized medicine. …

N-cadherin identifies human endometrial epithelial progenitor cells by in vitro stem cell assays.

STUDY QUESTION: Is there a specific surface marker that identifies human endometrial epithelial progenitor cells with adult stem cell activi … showed greater capacity for serial cloning (n = 7) and differentiated into cytokeratin+ gland-like organoids. N-cadherin immunolocalised to the lateral and apical membrane of epithelial cells in the bases of glands in the basalis of Pre-M endometrium and Post-M gland profiles, co-expressing cytokeratin, ERα but not SSEA-1 or SOX9, which localized on gland …

Advances in real-world research on fertility preservation in men with malignant tumours.

Malignant tumours have become one of the diseases that seriously threaten human health, and their incidence is increasing year by year. Worldwide, malignant tumours have become one of the most common causes of death in men. With the continuous progress of comprehensive oncological treatment, the cure rate and the survival rate of malignant tumours have been increasing, and the survival cycle has been prolonged, so the issue of fertility preservation in male malignant tumour patients has received widespread attention. In this review, researchers will discuss the real-world research progress rel

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… Testicular organoids and in-vitro spermatogenesis With the rapid development of biomedicine in recent years, research on testicular organoids and in-vitro spermatogenesis has gradually become a focus. … Testicular organoids are bioengineered organs that mimic the structure and function of the natural testis. Organoids with testicular characteristics are cultured in vitro by using bioengineering techniques with the help of SSCs and iPSCs ( 38 ). …

A Comparative Oncology Drug Discovery Pipeline to Identify and Validate New Treatments for Osteosarcoma.

BackgroundOsteosarcoma is a rare but aggressive bone cancer that occurs primarily in children. Like other rare cancers, treatment advances for osteosarcoma have stagnated, with little improvement in survival for the past several decades. Developing new treatments has been hampered by extensive genomic heterogeneity and limited access to patient samples to study the biology of this complex disease.MethodsTo overcome these barriers, we combined the power of comparative oncology with patient-derived models of cancer and high-throughput chemical screens in a cross-species drug discovery pipeline.R

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… Organoid models are also now being developed to test response to immunotherapies, as the organoids for several cancer types have been shown to contain infiltrating lymphocytes [ 24 , 25 ]. … Patient-derived organoids model treatment response of metastatic gastrointestinal cancers Science 2018 359 920 926 10.1126/science.aao2774 29472484 PMC6112415 18. Koga Y. Ochiai A. …

Contemporary Perspectives on Chronic Renal Disorders.

The prevalence of renal diseases and its associated burden on healthcare have tremendously risen in the past few years. From simple markers assessing kidney function, current renal research delves into understanding the diseases at the cellular and molecular levels and not just at treating, but at improving quality of life, arresting progression and providing personalized diagnostics and therapy. This narrative review highlights the improvements in diagnostic applications of kidney disease and briefly discusses a few notable biomarkers emphasizing the high throughput omics technologies, as wel

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… Organoids in Kidney Disease The limited availability of renal tissue for detailed study of structural and functional alterations in disease states makes 3D organoids essential tools for replicating the in vivo microenvironment. … It is imperative to address these concerns by implementing strategies to enhance the scalability of organoid cultures, facilitate the generation of specific cell types, and refine the vascularization of kidney organoids. …

Tumor microenvironment signaling and therapeutics in cancer progression.

Tumor development and metastasis are facilitated by the complex interactions between cancer cells and their microenvironment, which comprises stromal cells and extracellular matrix (ECM) components, among other factors. Stromal cells can adopt new phenotypes to promote tumor cell invasion. A deep understanding of the signaling pathways involved in cell-to-cell and cell-to-ECM interactions is needed to design effective intervention strategies that might interrupt these interactions. In this review, we describe the tumor microenvironment (TME) components and associated therapeutics. We discuss t

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… Since patient‐derived organoids (PDOs) consist of only epithelial cells, to develop a TME in organoids, either of the two approaches for organoid culture can be used: reconstituted the TME (submerged Matrigel culture) model or native TME (air‐liquid interface culture) model. … Moreover, the organoids derived from 2D monolayer cultures or mouse xenograft cultures differ from a primary organoid culture that retains cellular heterogeneity, tumor architecture, cell‐cell interactions, and stemness [ 377 ]. …

Time to evolve: predicting engineered T cell-associated toxicity with next-generation models.

Despite promising clinical results in a small subset of malignancies, therapies based on engineered chimeric antigen receptor and T-cell receptor T cells are associated with serious adverse events, including cytokine release syndrome and neurotoxicity. These toxicities are sometimes so severe that they significantly hinder the implementation of this therapeutic strategy. For a long time, existing preclinical models failed to predict severe toxicities seen in human clinical trials after engineered T-cell infusion. However, in recent years, there has been a concerted effort to develop models, in

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… Development of human 3D models (organoids, organotypical, organ-on-a-chip). … This idea has been used to assess the toxicity of CAR-NK92 cells against EGFRvIII and FRIZZLED using antigen-positive colon cancer organoids and normal colon organoids. 131 EGFRvIII-CAR showed selective cytotoxicity against colon cancer organoids. …