Large Cells Research Articles

Global machine learning potentials for molecular crystals.

Molecular crystals are difficult to model with accurate first-principles methods due to large unit cells. On the other hand, accurate modeling is required as polymorphs often differ by only 1kJ/mol. Machine learning interatomic potentials promise to provide accuracy of the baseline first-principles methods with a cost lower by orders of magnitude. Using the existing databases of the density functional theory calculations for molecular crystals and molecules, we train global machine learning interatomic potentials, usable for any molecular crystal. We test the performance of the potentials on experimental benchmarks and show that they perform better than classical force fields and, in some cases, are comparable to the density functional theory calculations.

In vitro evaluation of bone cell response to novel 3D-printable nanocomposite biomaterials for bone reconstruction.

Critically-sized segmental bone defects represent significant challenges requiring grafts for reconstruction. 3D-printed synthetic bone grafts are viable alternatives to structural allografts if engineered to provide appropriate mechanical performance and osteoblast/osteoclast cell responses. Novel 3D-printable nanocomposites containing acrylated epoxidized soybean oil (AESO) or methacrylated AESO (mAESO), polyethylene glycol diacrylate, and nanohydroxyapatite (nHA) were produced using masked stereolithography. The effects of volume fraction of nHA and methacrylation of AESO on interactions of differentiated MC3T3-E1 osteoblast (dMC3T3-OB) and differentiated RAW264.7 osteoclast cells with 3D-printed nanocomposites were evaluated in vitro and compared with a control biomaterial, hydroxyapatite (HA). Higher nHA content and methacrylation significantly improved the mechanical properties. All nanocomposites supported dMC3T3-OB cells' adhesion and proliferation. Higher amounts of nHA enhanced cell adhesion and proliferation. mAESO in the nanocomposites resulted in greater adhesion, proliferation, and activity at day 7 compared with AESO nanocomposites. Excellent osteoclast-like cells survival, defined actin rings, and large multinucleated cells were only observed on the high nHA fraction (30%) mAESO nanocomposite and the HA control. Thus, mAESO-based nanocomposites containing higher amounts of nHA have better interactions with osteoblast-like and osteoclast-like cells, comparable with HA controls, making them a potential future alternative graft material for bone defect repair.

The hydraulic characteristics of a subsurface flow stone biofilter for treating polluted runoff from an informal settlement

Abstract Polluted runoff from informal settlements in developing countries poses a growing challenge due to the elevated and variable nature of contaminants, particularly nutrients and pathogens, introduced to the environment. Cost-effective and scalable treatment systems with the ability to reduce nutrient and other pollutant concentrations in contaminated runoff are desirable. Biofilters are passive water treatment systems that have the potential to achieve this. The Franschhoek Water Hub, a research site for nature-based solutions, features six large biofiltration cells designed to remediate runoff from an informal settlement. Due to their large size, understanding hydraulic behaviour and validating the design proves challenging. To address this, a scaled-down version of the Water Hub's biofilters was constructed to inform design criteria for purpose-built filters. The pilot-scale subsurface flow biofilter, filled with 8–11 mm aggregate stone, had an available volume of 225 L. Pulse tracer studies conducted at various flow rates demonstrated that the system approximated plug flow behaviour. Lower flow rates resulted in deeper tracer infiltration, which is crucial for maximising the distribution of nutrients within the filter bed. This research contributes to the effective design and operation of biofiltration systems, which hold promise for addressing surface water contamination issues in resource-constrained regions.

Decoupling cell size homeostasis in diatoms from the geometrical constraints of the silica cell wall.

Unicellular organisms are known to exert tight control over their cell size. In the case of diatoms, abundant eukaryotic microalgae, two opposing notions are widely accepted. On the one hand, the rigid silica cell wall that forms inside the parental cell is thought to enforce geometrical reduction of the cell size. On the other hand, numerous exceptions cast doubt on the generality of this model. Here, we monitored clonal cultures of the diatom Stephanopyxis turris for up to 2 yr, recording the sizes of thousands of cells, in order to follow the distribution of cell sizes in the population. Our results show that S. turris cultures above a certain size threshold undergo a gradual size reduction, in accordance with the postulated geometrical driving force. However, once the cell size reaches a lower threshold, it fluctuates around a constant size using the inherent elasticity of cell wall elements. These results reconcile the disparate observations on cell size regulation in diatoms by showing two distinct behaviors, reduction and homeostasis. The geometrical size reduction is the dominant driving force for large cells, but smaller cells have the flexibility to re-adjust the size of their new cell walls.

Allometric Scaling Reveals Evolutionary Constraint on Odonata Wing Cellularity via Critical Crack Length.

Scaling in insect wings is a complex phenomenon that seems pivotal in maintaining wing functionality. In this study, the relationship between wing size and the size, location, and shape of wing cells in dragonflies and damselflies (Odonata) is investigated, aiming to address the question of how these factors are interconnected. To this end, WingGram, the recently developed computer-vision-based software, is used to extract the geometric features of wing cells of 389 dragonflies and damselfly wings from 197 species and 16 families. It has been found that the cell length of the wings does not depend on the wing size. Despite the wide variation in wing length (8.42 to 56.5 mm) and cell length (0.1 to 8.5 mm), over 80% of the cells hada length ranging from 0.5 to 1.5 mm, which waspreviously identified as the critical crack length of the membrane of locust wings. An isometric scaling of cells is also observed with maximum size in each wing, which increased as the size increased. Smaller cells tended to be more circular than larger cells. The results have implications for bio-mimetics, inspiring new materials and designs for artificial wings with potential applications in aerospace engineering androbotics.

Novel Ultrastructural Insights into the Clear-Cell Carcinoma of the Pancreas: A Case Report

Pancreatic cancer, most frequently as ductal adenocarcinoma (PDAC), is the third leading cause of cancer death. Clear-cell primary adenocarcinoma of the pancreas (CCCP) is a rare, aggressive, still poorly characterized subtype of PDAC. We report here a case of a 65-year-old male presenting with pancreatic neoplasia. A histochemical examination of the tumor showed large cells with clear and abundant intracytoplasmic vacuoles. The clear-cell foamy appearance was not related to the hyperproduction of mucins. Ultrastructural characterization with transmission electron microscopy revealed the massive presence of mitochondria in the clear-cell cytoplasm. The mitochondria showed disordered cristae and various degrees of loss of structural integrity. Immunohistochemistry staining for NADH dehydrogenase [ubiquinone] 1 alpha subcomplex, 4-like 2 (NDUFA4L2) proved specifically negative for the clear-cell tumor. Our ultrastructural and molecular data indicate that the clear-cell nature in CCCP is linked to the accumulation of disrupted mitochondria. We propose that this may impact on the origin and progression of this PDAC subtype.

Delicate chemical structure regulation of nonfullerene acceptor for efficient and large thickness organic solar cells

Delicate chemical structure regulation of nonfullerene acceptor for efficient and large thickness organic solar cells

ATML1 Regulates the Differentiation of ER Body-containing Large Pavement Cells in Rosette Leaves of Brassicaceae Plants.

Endoplasmic reticulum (ER)-derived organelles, ER bodies, participate in the defense against herbivores in Brassicaceae plants. ER bodies accumulate β-glucosidases, which hydrolyse specialized thioglucosides known as glucosinolates to generate bioactive substances. In Arabidopsis thaliana, the leaf ER (LER) bodies are formed in large pavement cells, which are found in the petioles, margins, and blades of rosette leaves. However, the regulatory mechanisms involved in establishing large pavement cells are unknown. Here, we show that the ARABIDOPSIS THALIANA MERISTEM L1 LAYER (ATML1) transcription factor regulates the formation of LER bodies in large pavement cells of rosette leaves. Overexpression of ATML1 enhanced the expression of LER body-related genes and the number of LER body-containing large pavement cells, whereas its knockout resulted in opposite effects. ATML1 enhances endoreduplication and cell size through LOSS OF GIANT CELLS FROM ORGANS (LGO). Although the overexpression and knockout of LGO affected the appearance of large pavement cells in Arabidopsis, the effect on LER body-related gene expression and LER body formation was weak. LER body-containing large pavement cells were also found in Eutrema salsugineum, another Brassicaceae species. Our results demonstrate that ATML1 establishes large pavement cells to induce LER body formation in Brassicaceae plants, and thereby possibly contributes to the defense against herbivores.

Recurrent cementoblastoma with multifocal growth and cellular atypia: a case report

BackgroundCementoblastoma is a rare odontogenic tumor characterized by the formation of osteocementum-like tissue on a tooth root directly by neoplastic cementoblasts. Although it is categorized as benign, it has a high potential for growth with a certain degree of recurrence risk. However, there are only a few studies describing the features of recurrent cementoblastoma. The diagnosis of recurrent cementoblastoma is challenging not only due to its cytological atypia but also because of its large size and multicentric growth pattern. These characteristics suggest a potential for malignancy.Case presentationA 29-year-old woman was transferred to our university dental hospital complaining of swelling of the right mandible. She had a history of enucleation of cementoblastoma associated with the third molar of the right mandible. Five years after the initial treatment, imaging demonstrated well-circumscribed multicentric radiopaque lesions in the same area. Histologically, the lesion consisted of osteocementum-like tissue rimmed with polygonal or plump tumor cells. Several cells were large epithelioid cells with bizarre nucleoli, which may be reminiscent of malignant tumors. Otherwise, there were no apparent malignant findings, including proliferative activity or atypical mitotic figure. Besides, tumor cells were positive for c-FOS, a marker of osteoblastoma and cementoblastoma. Eventually, the patient was diagnosed with recurrent cementoblastoma.ConclusionsPathological analyses of this case suggested that the recurrent event in the cementoblastoma altered its growth pattern and tumor cell shape. Moreover, in the case of enucleation surgery, long-term follow-up is important because there is some recurrent risk of cementoblastoma, although it is not high.

Cellular Distribution and Intracellular Localization of Different Sizes of Fluorescent Thiol-Organosilica Particles in Mouse Lungs.

We investigated the distribution of intratracheally administered thiol-organosilica (thiol-OS) particles in mouse lungs. Toward this end, single doses of thiol-OS particles containing fluorescein (140 nm in diameter) (F140) and rhodamine B (Rh) (Rh160, Rh280, Rh420, Rh640, and Rh1630 with diameters of 160, 280, 420, 640, and 1630 nm, respectively) were administered. After 24 h, fluorescence imaging revealed homogeneous fluorescence with a patchier pattern on the lung surface and no difference among the six particle sizes. Simultaneous dual administration of Rh and F140 particles did not reveal any size-dependent differences in the lung surface fluorescence. Fluorescence microscopy of the lung sections revealed a similar tissue distribution in the fluorescent areas of Rhs and F140. Some fluorescent areas showed one type of particle fluorescence or only one fluorescence. Cellular distribution of particles was observed in bronchoalveolar lavage cells and lung sections under a high magnification, and correlative light and electron microscopy revealed large cells with fluorescence corresponding to both particle types and small cells with fluorescence of individual particle types, indicating a cell-subset-dependent particle size effect. Rh280, Rh420, and Rh640 exhibited significant size effects and were taken up by alveolar macrophages. Extracellular particles were observed, indicating that saturation exceeded the particle dose threshold in the alveoli. F140 taken up by small and large macrophages colocalized with CD68, CD11c, and CD11b and correlated with CD11c. The size effect, intracellular localization, and extracellular distribution of particles provide insights into lung and systemic drug delivery.

Diffuse large B-cell lymphoma with DNA copy number changes in a Japanese black calf.

A 2-month-old Japanese Black calf exhibited mandibular and superficial cervical lymph node swelling. Fine needle aspiration cytology of the superficial cervical lymph node revealed large lymphoblast-like cells with mitoses. Hematological examination revealed remarkable lymphocytosis with atypical lymphocytes. Increased activities of serum total lactate dehydrogenase and thymidine kinase were detected. At necropsy, generalized swelling of lymph nodes was observed. Histopathological analysis revealed diffuse proliferation of medium-sized round centroblastic neoplastic cells that were positive for CD20, CD79α, PAX5, and BLA-36, and negative for CD3, CD5, CD10, and CD34. The calf was diagnosed with centroblastic diffuse large B-cell lymphoma (DLBCL) based on these findings. Analysis of DNA copy number variation revealed an increased copy number for the GIMAP family relative to that in healthy cattle. Moreover, decreases in copy numbers of GBP-1, MIR3141, OR5P1E, and PTPRG relative to those in healthy cattle were also observed. Because DNA copy number variation represent a major contribution to the somatic mutation landscapes in human tumors, these findings suggest that DNA copy number changes might have contributed to the onset of DLBCL in the present case.

Round-the-Clock and Continuous Generation of Hydrogen and Oxygen

The main methods of industrial hydrogen production are: steam restructuring of methane and natural gas; coal gasification; biotechnology; water electrolysis. The most efficient method for producing pure hydrogen and oxygen is to produce pure hydrogen and oxygen in a photoelectrochemical cell. A photoelectrochemical cell produces hydrogen and oxygen directly from solar energy. In a photoelectrochemical cell, a combined anode, made from silicon semiconductor and metal mesh with large cells, submerged in water electrolyte solution, agitated by four photons of light, forms an oxygen molecule, which in the form of a gas bubble lifts from the surface of anode to the free surface of the water electrolyte solution. Two hydrogen cations, formed because of the dissociation of water, reaching the cathode, form a gaseous hydrogen molecule, which, turn into an electrolysis bubble, lifts from surface of cathode to the free surface of the water electrolyte solution. The article presents a new method for round-the-clock and continuous generation of hydrogen and oxygen, using a developed photoelectrolyzer-generator, taking a horizontally located combine anode, made from silicon semiconductor and metal mesh with large cells and burnt graphite cathode (electrolysis base) at the bottom of the photoelectrolyzer-generator; a membrane from fire hose material, located between electrodes; device, regulating the gap between the electrodes. Round-the-clock and continuous production of hydrogen and oxygen in the photoelectrolyzer-generator is ensured by using lamp, including LED with a daylight battery charger as a useful electrical load, which brightens the combined anode, made from silicon semiconductor and metal mesh with large cells at night until the morning and by continuously filling the photoelectrolyzer-generator with water.

Extracellular Microvesicles Modified with Arginine-Rich Peptides for Active Macropinocytosis Induction and Delivery of Therapeutic Molecules.

Extracellular vesicles (EVs), including exosomes and microvesicles (MVs), transfer bioactive molecules from donor to recipient cells in various pathophysiological settings, thereby mediating intercellular communication. Despite their significant roles in extracellular signaling, the cellular uptake mechanisms of different EV subpopulations remain unknown. In particular, plasma membrane-derived MVs are larger vesicles (100 nm to 1 μm in diameter) and may serve as efficient molecular delivery systems due to their large capacity; however, because of size limitations, receptor-mediated endocytosis is considered an inefficient means for cellular MV uptake. This study demonstrated that macropinocytosis (lamellipodia formation and plasma membrane ruffling, causing the engulfment of large fluid volumes outside cells) can enhance cellular MV uptake. We developed experimental techniques to induce macropinocytosis-mediated MV uptake by modifying MV membranes with arginine-rich cell-penetrating peptides for the intracellular delivery of therapeutic molecules.

Plasmablastic Lymphoma and Plasmablastic Myeloma: А Diagnostic Dilemma (Literature Review)

Plasmablastic lymphoma and plasmablastic myeloma are similar in morphology. Tumor substrate in both is characterized by large cells with blastic morphology, central or somewhat eccentric nuclei, large central nucleolus or some distinct nucleoli, and abundant eosinophilic cytoplasm. The common characteristic of both B-cell tumors is the expression of plasma cell differentiation markers (CD38, CD138, MUM-1/IRF-4, interferon regulatory factor 4, PRDM-1, PR domain zinc finger protein 1, and/or XBP-1, X-box-1 binding protein) with a frequent loss of CD20. These rare nosological entities with similar morphological and immunohistochemical features present a challenge for differential and reliable diagnosis. The present review deals with clinical signs, diagnostically significant immunohistochemical markers, and molecular genetic characteristics which are essential for differential diagnosis of plasmablastic lymphoma and plasmablastic myeloma.

Assessing Postpartum Reproductive Health via Endometrial Cytology and Body Temperature in Mehsana Buffaloes

The aim of this study was to investigate the effect of body temperature and endometrial cytology on postpartum reproductive health in Mehsana buffaloes. A total of twenty-six Mehsana buffaloes were used in this study. Per-rectal and ultrasonography examinations were used to observe the postpartum reproductive function of these buffaloes and on day 60 post natural service, the pregnancy was confirmed. Based on fertile estrus, buffaloes were retrospectively divided into two groups: Group I (buffaloes conceiving before 90 days) and Group II (buffaloes conceiving after 90 days). One week before parturition and four weeks after it, the rectal temperature was taken. The cytobrush technique was used to obtain endometrial samples for cytological tests on the 21st and 30th day postpartum. During the final week of pregnancy and the first, second, third, and fourth weeks’ post-partum, the mean rectal temperature (⁰F) varied from 101.7 ± 0.07 to 102.0 ± 0.06 in Group-I and 101.6 ± 0.07 to 102.1 ± 0.05 in Group-II. During the final week pre-partum and the first week post-partum, the mean rectal temperature (⁰F) was shown to be significantly (p<0.05) lower than it was during the second, third, and fourth weeks post-partum among the groups. On the 21st and 30th day postpartum during endometrial cytology, the percentage of neutrophils was 14.31 ± 1.56 and 12.23 ± 0.93 in Group I and 17.92 ± 1.51 and 15.08 ± 0.73 in Group II, respectively. On the 30th day, there was a significant difference (p<0.05) between the groups in Group II that had a greater mean percentage of neutrophils. When endometrial cytology was performed on buffaloes at various postpartum days, the mean percentage of lymphocytes, endometrial epithelial cells and large vacuolated epithelial cells revealed non-significant changes. On the 30th day, it was discovered that the prevalence of subclinical endometritis in Group I and Group II buffaloes was 7.69 and 23.07 percent, respectively. The postpartum first behavioural estrus and first fertile estrus occurred at 62.00 ± 4.34 and 65.31±4.45 days in Group I and 77.46±11.12 and 130.08±9.26 days in Group II buffaloes, respectively. Although, the average days for first behavioural estrus did not differ significantly between the groups the fertile estrus occurred significantly (P<0.05) delayed in Group II buffaloes.

Glioblastoma, IDH-Wildtype With Epithelioid Morphology and a BCR::NTRK2 Fusion.

Glioblastoma, IDH-wildtype (GBM) is a high-grade astrocytic glioma that accounts for the majority of malignant brain tumors in adults. Within this entity, epithelioid GBM represents a histological subtype characterized by a loosely cohesive aggregate of large cells with abundant cytoplasm, and vesicular nuclei that usually harbors the BRAF V600E mutation. Molecular alterations in GBMs are frequent and play an important role in the diagnosis of this entity. Among the many genetic alterations reported, NTRK fusions are rare and account for <2% of gliomas. Furthermore, NTRK2 fusions are most seen in pediatric populations. Recent approval of the TRK inhibitor larotrectinib by the Food and Drug Administration (FDA) has brought interest in the study and recognition of NTRK fusions in multiple types of tumors. Trials that assess the response to this drug in cancers carrying NTRK fusions have yielded favorable results. We discuss a rare presentation of an adult-type GBM with epithelioid morphology and a BCR::NTRK2 gene fusion.

Lymphomatoid Papulosis With T-cell Receptor-Gamma Delta Expression: A Clinicopathologic Case-series of 26 Patients of an Underrecognized Immunophenotypic Variant of Lymphomatoid Papulosis.

Lymphomatoid papulosis (LyP) has several histopathologic presentations. LyP featuring gamma-delta (γδ) T-cell receptor expression may masquerade as and may be misdiagnosed as aggressive cutaneous T-cell lymphoma, particularly primary cutaneous γδ T-cell lymphoma (PCGDTL) or γδ mycosis fungoides. We performed a clinicopathologic analysis of the largest series of LyP featuring γδ T-cell expression. We identified 26 patients with a diagnosis of LyP with γδ T cells from our institutions, as well as through a comprehensive review of the literature, and characterized these cases. Most cases were treated with topical steroids or not treated at all. The majority of cases showed a CD4-CD8+ phenotype and featured at least one cytotoxic marker. Histopathologic features included an intraepidermal or dermal infiltrate with large cells and frequent angiotropism. One case was initially misdiagnosed as PCGDTL, requiring further therapy. Our case series, the largest international cohort of γδ T cell predominant LyP cases, confirms marked clinicopathologic heterogeneity that may contribute to misdiagnosis, reasserting the need to identify classic clinical features, CD30+ T-cell components, and markers of cytotoxicity when dealing with this differential diagnosis. A limitation of this study includes somewhat limited follow-up, histologic, and immunophenotypic information for some cases.

Follicular dendritic cell sarcoma arising from the lymph node of the pancreatic head: a case report with literature review.

A 72-year-old man was referred to our hospital for the examination of a pancreatic head mass. Abdominal computed tomography revealed a contrasted 8-cm-diameter tumor extending from the dorsal pancreatic head to the porta hepatis. The preoperative diagnosis was challenging due to the absence of specific imaging findings and the inability to perform a biopsy. Positron emission tomography/computed tomography and diffusion-weighted imaging suggested a malignant tumor originating from the organs surrounding the pancreatic head. Subtotal stomach-preserving pancreaticoduodenectomy with regional lymph node dissection was performed, as dissection from the pancreatic head proved unfeasible. Pathological examination identified the tumor as an enlarged lymph node consisting of pleomorphic large cells forming clusters, positive for follicular dendritic cell markers cluster of differentiation (CD) 21 and CD23. No evidence of tumor capsule infiltration, other organ infiltration, or metastasis to other lymph nodes was observed. The final diagnosis was nodal follicular dendritic cell sarcoma (FDCS) originating from the pancreatic head lymph nodes. No recurrence occurred at 3years postoperatively with no postoperative treatment. Intraperitoneal nodal FDCS is extremely rare, and occasionally, it can lead to postoperative recurrence and progression. It is crucial to differentiate neoplastic lymph node enlargement around the pancreatic head from nodal FDCS.

Abstract 5281: 5-Fluorouracil decreases MDSC and the development of osteolytic bone metastases from breast cancer in mice

Abstract Bone metastases are a highly debilitating complication in more than 70% of patients with advanced breast and prostate cancer. Currently approved treatments fail to cure bone metastases or increase patient survival. Although immunotherapies can cause a durable response in some patients, it seems that their efficacy is limited in bone metastases, which could be due to a cold metastatic microenvironment. Our aim was to identify immunosuppressive factors in bone metastases and target them using a drug-repositioning type approach. We used a syngeneic model in which 4T1 triple-negative breast cancer cells derived from a Balb/C mouse are inoculated in the left cardiac ventricle of Balb/C mice to cause osteolytic bone metastases. Using flow cytometry, we found that the bone marrow of mice with 4T1 bone metastases is enriched in large cells with a high SSC index that could be myeloid-derived suppressor cells. We confirmed that the inoculation of 4T1 cells increased the amount of CD11b+ Ly6G+ Ly6Clo ROShi and CD11b+ Ly6G- Ly6Chi NOhi cells. Both cell types were isolated from bone metastases and prevented the proliferation of CD8+ T cells ex vivo, confirming they were polymorphonuclear- (PMN-) and monocytic-MDSCs (M-MDSCs), respectively. In addition, both types could differentiate into osteoclasts that cause bone loss. Reviewing the current literature, we found that FDA-approved sildenafil (a PDE-5 inhibitor), zoledronic acid (a bone resorption inhibitor), and 5-fluorouracil (5-FU, a chemotherapeutic agent) can decrease MDSCs in other cancer models. However, sildenafil (20mg/kg, i.p., every 2 days) and zoledronic acid (25µg/kg, s.c., 3x/week) did not decrease the amount of MDSCs in 4T1 bone metastases. 5-FU (i.p., 4 inoculations) at 50mg/kg prevented the 4T1-induced splenomegaly and the increase of PMN- and M-MDSCs but seemed to decrease the number of T cells in bone metastases. Thus, we tested the efficacy of a lower number of inoculations. A single inoculation of 5-FU was not efficient, while 2 or 3 inoculations of 5-FU (50mg/kg) prevented the splenomegaly and the histological damage due to extramedullary hematopoiesis in the spleen. In 4T1 bone metastases, there was a decrease of PMN-MDSCs and an increase of the number of CD4+ and CD8+ T cells. On radiographs, 2 or 3 inoculations of 5-FU (50mg/kg) significantly decreased the area of the osteolytic lesions caused by 4T1 cells (-57% and -60%, respectively, compared to placebo, P&amp;lt;0.005). In conclusion, our results show that functional PMN- and M-MDSCs can increase and accumulate in the microenvironment of breast cancer bone metastases and that an optimized treatment with 5-FU can prevent this expansion of MDSC, increasing T cell infiltration in bone metastases and decrease the associated bone lesions. Treatment with 5-FU could then contribute to turning bone metastases from a cold to a hot microenvironment and increase the efficacy of immunotherapies in patients. Citation Format: Pierrick G.J. Fournier, Paloma Almeida Luna, Danna Arellano, Samanta Jiménez, Felipe Olvera, Patricia Juárez. 5-Fluorouracil decreases MDSC and the development of osteolytic bone metastases from breast cancer in mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5281.

Artesunate induces ferroptosis by regulating MT1G and has an additive effect with doxorubicin in diffuse large B-cell lymphoma cells

Diffuse Large B-cell lymphoma (DLBCL) is a highly aggressive disease with heterogeneous outcomes and marked variability in the response to chemotherapy. DLBCL comprises two major subtypes: germinal centre B-cell-like (GCB) and activated B-cell-like (ABC). Our study highlights the extensive antitumour activity of artesunate (ART) against both major DLBCL subtypes. Transcriptome analysis suggests the potential involvement of ferroptosis in artesunate-induced cell death. Because of low glutathione (GSH) and glutathione peroxidase 4 (GPX4) levels, along with the accumulation of free iron (Fe2+), artesunate induces the excessive production of reactive oxygen species (ROS), ultimately leading to ferroptosis, a form of cell death driven by phospholipid peroxidation. A putative target of artesunate, metallothionein 1G (MT1G), was selected for further analysis. Subsequent studies revealed that inhibiting MT1G expression in vitro significantly impedes the ferroptosis-promoting activity of artesunate by reducing lipid peroxidation and iron accumulation. We also showed that the combination of artesunate and doxorubicin had a marked additive inhibitory effect on GCB and ABC DLBCL cells. In conclusion, artesunate induces ferroptotic death in GCB and ABC DLBCL cells by attenuating the GPX4/GSH antioxidant defence system and increasing intracellular iron levels, indicating its therapeutic potential for relapsed or refractory DLBCL.