scholarly journals InVivo Molecular Ultrasound Assessment of Glioblastoma Neovasculature with Endoglin-Targeted Microbubbles

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Cheng Liu ◽  
Fei Yan ◽  
Yajie Xu ◽  
Hairong Zheng ◽  
Lei Sun
Keyword(s):  
Ex Vivo ◽  
Tumor Model ◽  
Flow Chamber ◽  
Parallel Flow ◽  
Expression Levels ◽  
Subcutaneous Xenograft ◽  
Molecular Ultrasound ◽  
Noninvasive Assessment ◽  
Ultrasound Signals

Objectives. Glioblastoma, as one of the most malignant cancer in the world, usually shows substantially increased angiogenesis. Endoglin (CD105), which is an alternative proangiogenic growth factor, has been remarkably upregulated on the proliferating glioblastoma neovasculature. However, little is known on the noninvasive assessment of the expression levels of CD105 during glioblastoma progression. Herein, we investigated the potential of the molecular ultrasound imaging for the noninvasive assessment of the expression levels of the biomarker CD105 during the glioblastoma progression. Materials and Methods. The CD105-targeted perfluorocarbon-containing lipid-shelled microbubbles (MBs) were prepared. A parallel flow chamber was employed, in which the CD105-targeted and non-targeted MBs were tested across the CD105 ± expression cell lines. In vivo molecular US imaging was conducted based on a subcutaneous xenograft tumor model (n=9). Finally, the statistical analysis was conducted to quantitatively correlate the attachment numbers of MBs in the parallel flow chamber test with the CD105 expression levels of the cells in the flow cytometry test and the in vivo molecular ultrasound signals with the ex vivo expression levels of CD105 in the immunohistochemical test. Results and Discussion. The attachment numbers of the CD105-targeted MBs significantly correlated with the CD105 expression levels of the cells in the parallel flow chamber test. There was a good correlation between the in vivo molecular ultrasound signals with the CD105-targeted MBs and the ex vivo expression levels of CD105 in the immunohistochemical test. The results indicate that the molecular US imaging is much potential to assess the progression of the glioblastoma neovasculature noninvasively.

Abstract 54: ML355 in Prevention of Thrombosis in vivo with Minimal Effects on Hemostasis

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Reheman Adili ◽  
Katherine Mast ◽  
Michael Holinstat
Keyword(s):  
Ex Vivo ◽  
Platelet Reactivity ◽  
Thrombus Formation ◽  
Flow Chamber ◽  
Human Platelets ◽  
Mass Spectrometry Analysis ◽  
Vessel Occlusion ◽  
Spectrometry Analysis ◽  
Thrombosis Model

12-lipoxygenase (12-LOX) has been demonstrated to regulate platelet function, hemostasis, and thrombosis ex vivo , supporting a key role for 12-LOX in regulation of in vivo thrombosis. While pharmacologically targeting 12-LOX in vivo has been a challenge to date, the recent development of the 12-LOX selective inhibitor, ML355, as an effective antiplatelet therapeutic in vivo was assessed. ML355 potently inhibited thrombin and other agonist-induced platelet aggregation ex vivo in washed human platelets and inhibited downstream oxylipin production of platelet 12-LOX as confirmed by Mass spectrometry analysis. Ex vivo flow chamber assays confirmed that human platelet adhesion and thrombus formation at arterial shear over collagen was attenuated in human whole blood treated with ML355 to a greater extent compared to aspirin. In vivo , PK assessment of ML355 showed reasonable 12-LOX plasma levels 12 hours following administration of ML355. FeCl 3 -induced injury of the mesenteric arterioles resulted in less stable thrombi in 12-LOX -/- mice and ML355-treated WT mice resulting in impairment of vessel occlusion. Additionally, ML355 dose-dependently inhibited laser-induced thrombus formation in the cremaster arteriole thrombosis model in WT, but not in 12-LOX -/- mice. Importantly, hemostatic plug formation and bleeding following treatment with ML355 were not affected in response to laser ablation on the saphenous vein or in a cremaster microvasculature laser-induced rupture model. Our data strongly supports 12-LOX as a key determinant of platelet reactivity in vivo and inhibition of platelet 12-LOX with ML355 may represent a new class of antiplatelet therapeutics.

5 Cold stored platelets correct cardiac surgery induced platelet dysfunction

2021 ◽  
Vol 167 (3) ◽  
pp. e1.5-e1
Author(s):  
Tom Scorer ◽  
Andrew Mumford
Keyword(s):  
Cardiac Surgery ◽  
Shelf Life ◽  
Platelet Function ◽  
Platelet Transfusion ◽  
Ex Vivo ◽  
Flow Chamber ◽  
Platelet Dysfunction ◽  
Current Standard ◽  
Blood Samples

IntroductionPlatelet dysfunction (thrombocytopathy) is a major problem in the bleeding patient and increases morbidity and healthcare costs. The thrombocytopathy resulting from cardiopulmonary bypass (CPB) can be used to study therapies targeted to improve outcomes in other scenarios, such as trauma. Platelet transfusion is used widely to correct thrombocytopathy. However, the current standard, room temperature stored platelets (RTP) have several disadvantages including; short shelf life, risk of bacterial contamination and deterioration in platelet function during storage. Cold stored platelets (CSP) are a potential alternative product with longer shelf life, reduced contamination risk and better-preserved platelet function.MethodsUsing ex vivo mixing studies, we investigated whether CSP were better able to reverse the thrombocytopathy associated with cardiac surgery than RTP. Blood samples were collected from 20 cardiac surgery patients. Donor platelets were split into two bags and stored at either 4°C (CSP), or 22°C (RTP) for up to seven days. The donor platelets were mixed with the patient blood samples to simulate platelet transfusion. The mixed samples were analysed using the TEG 5000 and using a collagen coated flow chamber at arterial shear. Patient samples were analysed alongside healthy controls (n = 20).ResultsAfter mixing the patient samples with CSP, the TEG R times were shorter than in samples mixed with RTP (p<0.0001), indicating more rapid initiation of clot formation. In the flow chamber experiments, the clot volume was greater in the patient samples mixed with CSP compared with samples mixed with RTP (p<0.0001).ConclusionsThese findings suggest that CSP, but not RTP can partially reverse the thrombocytopathy associated with cardiac surgery ex vivo, at clinically relevant mixing volumes. Reversal of thrombocytopathy by mixing CSP was greatest in the arterial shear model, which may indicate superior in vivo efficacy that requires confirmation in clinical trials.* this abstract presentation was awarded First Place.

scholarly journals Alpha-tocopherol, an effective inhibitor of platelet adhesion

Blood ◽  
1989 ◽  
Vol 73 (1) ◽  
pp. 141-149 ◽  
Author(s):  
J Jandak ◽  
M Steiner ◽  
PD Richardson
Keyword(s):  
Vitamin E ◽  
Platelet Adhesion ◽  
Ex Vivo ◽  
Platelet Rich Plasma ◽  
Flow Chamber ◽  
Alpha Tocopherol ◽  
Tocopherol Concentration ◽  
Average Decrease ◽  
Platelet Adherence

Abstract Platelet adhesiveness was tested ex vivo in a group of six normal individuals receiving varying doses of alpha-tocopherol. Adhesion to glass slides coated with fibronectin, collagen, fibrinogen, or plasma proteins was studied by perfusing platelet-rich plasma through a flow chamber that allowed time- and space-resolved observations of platelet adhesion. Platelet adherence was measured in an area of parallel flow lines and low shear rate under standardized conditions before and after dietary supplementation with vitamin E at doses of 200 and 400 IU/d. Platelet adherence differed in magnitude depending on the adhesive surface. There was a distinct preference of platelets to adhere to sites that had been previously occupied. A remarkable decrease in platelet adherence was observed after vitamin E supplementation. The average decrease in adhesion after 2 weeks of 200 IU vitamin E was 75%. After 2 weeks of 400 IU vitamin E, platelet adhesion was reduced by 82%. The inhibitory activity of alpha-tocopherol was dose dependent and correlated well with the increase in alpha-tocopherol concentration in platelets after supplementation. Scanning electron microscopy revealed a striking decrease of pseudopodium formation in alpha-tocopherol- enriched platelets. Our results suggest that vitamin E may also be an effective antiadhesive agent in vivo.

Alpha-tocopherol, an effective inhibitor of platelet adhesion

Blood ◽  
1989 ◽  
Vol 73 (1) ◽  
pp. 141-149
Author(s):  
J Jandak ◽  
M Steiner ◽  
PD Richardson
Keyword(s):  
Vitamin E ◽  
Platelet Adhesion ◽  
Ex Vivo ◽  
Platelet Rich Plasma ◽  
Flow Chamber ◽  
Alpha Tocopherol ◽  
Tocopherol Concentration ◽  
Average Decrease ◽  
Platelet Adherence

Platelet adhesiveness was tested ex vivo in a group of six normal individuals receiving varying doses of alpha-tocopherol. Adhesion to glass slides coated with fibronectin, collagen, fibrinogen, or plasma proteins was studied by perfusing platelet-rich plasma through a flow chamber that allowed time- and space-resolved observations of platelet adhesion. Platelet adherence was measured in an area of parallel flow lines and low shear rate under standardized conditions before and after dietary supplementation with vitamin E at doses of 200 and 400 IU/d. Platelet adherence differed in magnitude depending on the adhesive surface. There was a distinct preference of platelets to adhere to sites that had been previously occupied. A remarkable decrease in platelet adherence was observed after vitamin E supplementation. The average decrease in adhesion after 2 weeks of 200 IU vitamin E was 75%. After 2 weeks of 400 IU vitamin E, platelet adhesion was reduced by 82%. The inhibitory activity of alpha-tocopherol was dose dependent and correlated well with the increase in alpha-tocopherol concentration in platelets after supplementation. Scanning electron microscopy revealed a striking decrease of pseudopodium formation in alpha-tocopherol- enriched platelets. Our results suggest that vitamin E may also be an effective antiadhesive agent in vivo.

Dendritic cells modified to express CD40 ligand elicit therapeutic immunity against preexisting murine tumors

Blood ◽  
2000 ◽  
Vol 96 (1) ◽  
pp. 91-99 ◽  
Author(s):  
Toshiaki Kikuchi ◽  
Malcolm A. S. Moore ◽  
Ronald G. Crystal
Keyword(s):  
Dendritic Cells ◽  
Cytotoxic T Lymphocyte ◽  
Tumor Regression ◽  
Ex Vivo ◽  
Tumor Model ◽  
Adenovirus Vector ◽  
Cd40 Ligand ◽  
Murine Tumors

CD40 ligand (CD40L) is essential for the initiation of antigen-specific T-cell responses. This study is based on the hypothesis that dendritic cells (DCs) genetically modified ex vivo to express CD40L will enhance in vivo presentation of tumor antigen to the cellular immune system with consequent induction of antitumor immunity to suppress tumor growth. To examine this concept, subcutaneous murine tumors were injected with bone marrow-derived DCs that had been modified in vitro with an adenovirus (Ad) vector expressing murine CD40L (AdmCD40L). In B16 (H-2b, melanoma) and CT26 (H-2d, colon cancer) murine models, intratumoral injection of 2 × 106 AdmCD40L-modified DCs (CD40L-DCs) to established (day 8) subcutaneous tumors resulted in sustained tumor regression and survival advantage. This antitumor effect was sustained when the number of CD40L-DCs were reduced 10-fold to 2 × 105. Analysis of spleens from CD40L-DC–treated animals demonstrated that CD40L-DCs injected into the subcutaneous CT26 flank tumors migrated to the spleen, resulting in activation of immune-relevant processes. Consistent with this concept, intratumoral administration of CD40L-DCs elicited tumor-specific cytotoxic T-lymphocyte responses, and the transfer of spleen cells from CD40L-DC–treated mice efficiently protected naive mice against a subsequent tumor challenge. In a distant 2-tumor model of metastatic disease, an untreated B16 tumor in the right flank regressed in parallel with a left B16 tumor treated with direct injection of CD40L-DCs. These results support the concept that genetic modification of DCs with a recombinant CD40L adenovirus vector may be a useful strategy for directly activating DCs for cancer immunotherapy.

scholarly journals Anti-Tumoral and Anti-Angiogenic Effects of Low-Diluted Phenacetinum on Melanoma

2021 ◽  
Vol 11 ◽  
Author(s):  
Camille Fuselier ◽  
Sandrine Quemener ◽  
Eleonore Dufay ◽  
Camille Bour ◽  
Camille Boulagnon-Rombi ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Side Effects ◽  
Ex Vivo ◽  
Tumor Model ◽  
Primary Cutaneous Melanoma ◽  
Relieve Pain ◽  
Melanoma Treatment ◽  
Vertical Growth Phase

Melanoma is the most aggressive form of skin cancer and the most rapidly expanding cancer in terms of worldwide incidence. If primary cutaneous melanoma is mostly treated with a curative wide local excision, malignant melanoma has a poor prognosis and needs other therapeutic approaches. Angiogenesis is a normal physiological process essential in growth and development, but it also plays a crucial role in crossing from benign to advanced state in cancer. In melanoma progression, angiogenesis is widely involved during the vertical growth phase. Currently, no anti-angiogenic agents are efficient on their own, and combination of treatments will probably be the key to success. In the past, phenacetin was used as an analgesic to relieve pain, causing side effects at large dose and tumor-inducing in humans and animals. By contrast, Phenacetinum low-dilution is often used in skin febrile exanthema, patches profusely scattered on limbs, headache, or flushed face without side effects. Herein are described the in vitro, in vivo, and ex vivo anti-angiogenic and anti-tumoral potentials of Phenacetinum low-dilution in a B16F1 tumor model and endothelial cells. We demonstrate that low-diluted Phenacetinum inhibits in vivo tumor growth and tumor vascularization and thus increases the survival time of B16F1 melanoma induced-C57BL/6 mice. Moreover, Phenacetinum modulates the lung metastasis in a B16F10 induced model. Ex vivo and in vitro, we evidence that low-diluted Phenacetinum inhibits the migration and the recruitment of endothelial cells and leads to an imbalance in the pro-tumoral macrophages and to a structural malformation of the vascular network. All together these results demonstrate highly hopeful anti-tumoral, anti-metastatic, and anti-angiogenic effects of Phenacetinum low-dilution on melanoma. Continued studies are needed to preclinically validate Phenacetinum low-dilution as a complementary or therapeutic strategy for melanoma treatment.

scholarly journals Preclinical Rationale for Targeting the PD-1/PD-L1 Axis in Combination with a CD38 Antibody in Multiple Myeloma and Other CD38-Positive Malignancies

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3713
Author(s):  
Christie P. M. Verkleij ◽  
Amy Jhatakia ◽  
Marloes E. C. Broekmans ◽  
Kristine A. Frerichs ◽  
Sonja Zweegman ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
T Cell ◽  
Ex Vivo ◽  
Suppressor Cells ◽  
Newly Diagnosed ◽  
Short Term ◽  
Expression Levels ◽  
Cell Immunity

The CD38-targeting antibody daratumumab mediates its anti-myeloma activities not only through Fc-receptor-dependent effector mechanisms, but also by its effects on T-cell immunity through depletion of CD38+ regulatory T-cells, regulatory B-cells, and myeloid-derived suppressor cells. Therefore, combining daratumumab with modulators of other potent immune inhibitory pathways, such as the PD-1/PD-L1 axis, may further improve its efficacy. We show that multiple myeloma (MM) cells from relapsed/refractory patients have increased expression of PD-L1, compared to newly diagnosed patients. Furthermore, PD-1 is upregulated on T-cells from both newly diagnosed and relapsed/refractory MM patients, compared to healthy controls. In short-term experiments with bone marrow samples from MM patients, daratumumab-mediated lysis was mainly associated with the MM cells’ CD38 expression levels and the effector (NK-cells/monocytes/T-cells)-to-target ratio, but not with the PD-L1 expression levels or PD-1+ T-cell frequencies. Although PD-1 blockade with nivolumab did not affect MM cell viability or enhanced daratumumab-mediated lysis in short-term ex vivo experiments, nivolumab resulted in a mild but clear increase in T-cell numbers. Moreover, with a longer treatment duration, PD-1 blockade markedly improved anti-CD38 antibody-mediated cytotoxicity in vivo in murine CD38+ tumor models. In conclusion, dual targeting of CD38 and PD-1 may represent a promising strategy for treating MM and other CD38-positive malignancies.

High-Vorticity with Periodic Flow Enhances in Vitro Biogenesis of Healthy Platelets from iPSC-Derived-Megakaryocytes

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2181-2181
Author(s):  
Yukitaka Ito ◽  
Sou Nakamura ◽  
Tomohiro Shigemori ◽  
Naoshi Sugimoto ◽  
Yoshikazu Kato ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Steady State ◽  
Ex Vivo ◽  
Annexin V ◽  
Poor Quality ◽  
Flow Chamber ◽  
Physical Parameters ◽  
Platelet Production

Abstract Each transfusion requires 200-300 billion platelets in patients with thrombocytopenia. To continuously supply such a huge number of platelets by ex vivo generation, two distinct steps, megakaryopoiesis and platelet shedding, must be both considered. For the former, one approach is to increase the number of source cell, megakaryocytes. For example, the immortalized megakaryocyte cell line (imMKCL) system uses self-renewing megakaryocyte (MK) cell lines derived from induced pluripotent stem cells (iPSCs) (Nakamura et al., Cell Stem Cell, 2014). For the latter, there have been an idea of bioreactors whereby shedding of platelets from proplatelets could be promoted by flow-dependent shear force within the bone marrow in vivo (Junt et al., Science, 2007; Zhang et al., J Exp Med, 2012). Based upon this idea, we constructed a flow chamber type bioreactor recapitulating in vivo blood flow shear rate. However, this bioreactor failed to efficiently yield platelets, and moreover, the produced platelets had poor quality as indicated by high Annexin V levels (Exp Hematol, 2011 and unpublished result). Recently, we demonstrated two different kinetics of platelet biogenesis from bone marrow MKs, whereby either thrombopoietin (TPO) mostly regulates steady-state shedding of platelets from proplatelets, or interleukin-a (IL-1a) triggers inflammation-dependent rupture of MK cytoplasm contributing to a quick increase of platelet count at higher rate (Nishimura et al., J Cell Biol, 2015). However, the rupture type platelets revealed shorter half-life with relatively higher Annexin V levels. Therefore, to gain insights from platelet biogenesis in vivo, we focused on biophysical analysis of steady-state platelet biogenesis via proplatelets in bone marrow. Our observations strongly indicated that the presence of 'vorticity' defined by vortex turbulence in addition to shear-dependent 'stress' and 'strain' correlates with the efficient shedding of competent platelets. From this new finding, we developed an alternative bioreactor system, which enabled generation of 100 billion platelets from imMKCL in a 16L-scale liquid culture condition without any adherent machinery using two 10L-bioreactors. Furthermore, platelets generated via new bioreactors showed low Annexin V levels (<10-15%) and shortened bleeding time post transfusion into NOG mice and rabbits with thrombocytopenia, comparable to human blood product platelets. Regarding the platelet production using WAVE bag system (GE healthcare, UK), the system is already clinically available for cord blood cell expansion in most countries, but lacks adequate levels of vorticity and shear strain/stress. Accordingly, the produced platelets had high Annexin V levels (i.e., 50-65%) as well as diminished yield efficiency (P<0.001). In conclusion, our study has uncovered the novel biophysical aspect of platelet biogenesis. The application of the new set of physical parameters in constructing large sized bioreactors shall facilitate the industrialization of platelet production. Disclosures Eto: Megakaryon Co. Ltd.: Research Funding.

scholarly journals [18F]FDG Uptake in Adipose Tissue Is Not Related to Inflammation in Type 2 Diabetes Mellitus

2020 ◽  
Vol 23 (1) ◽  
pp. 117-126
Author(s):  
Melanie Reijrink ◽  
Stefanie A. de Boer ◽  
Ines F. Antunes ◽  
Daan S. Spoor ◽  
Hiddo J. L. Heerspink ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Mrna Expression ◽  
Ex Vivo ◽  
Expression Levels ◽  
Fdg Uptake ◽  
Mrna Expression Levels

Abstract Purpose 2-deoxy-2-[18F]fluoro-d-glucose ([18F]FDG) uptake is a marker of metabolic activity and is therefore used to measure the inflammatory state of several tissues. This radionuclide marker is transported through the cell membrane via glucose transport proteins (GLUTs). The aim of this study is to investigate whether insulin resistance (IR) or inflammation plays a role in [18F]FDG uptake in adipose tissue (AT). Procedures This study consisted of an in vivo clinical part and an ex vivo mechanistic part. In the clinical part, [18F]FDG uptake in abdominal visceral AT (VAT) and subcutaneous AT (SAT) was determined using PET/CT imaging in 44 patients with early type 2 diabetes mellitus (T2DM) (age 63 [54–66] years, HbA1c [6.3 ± 0.4 %], HOMA-IR 5.1[3.1–8.5]). Plasma levels were measured with ELISA. In the mechanistic part, AT biopsies obtained from 8 patients were ex vivo incubated with [18F]FDG followed by autoradiography. Next, a qRT-PCR analysis was performed to determine GLUT and cytokine mRNA expression levels. Immunohistochemistry was performed to determine CD68+ macrophage infiltration and GLUT4 protein expression in AT. Results In vivo VAT [18F]FDG uptake in patients with T2DM was inversely correlated with HOMA-IR (r = − 0.32, p = 0.034), and positively related to adiponectin plasma levels (r = 0.43, p = 0.003). Ex vivo [18F]FDG uptake in VAT was not related to CD68+ macrophage infiltration, and IL-1ß and IL-6 mRNA expression levels. Ex vivo VAT [18F]FDG uptake was positively related to GLUT4 (r = 0.83, p = 0.042), inversely to GLUT3 (r = − 0.83, p = 0.042) and not related to GLUT1 mRNA expression levels. Conclusions In vivo [18F]FDG uptake in VAT from patients with T2DM is positively correlated with adiponectin levels and inversely with IR. Ex vivo [18F]FDG uptake in AT is associated with GLUT4 expression but not with pro-inflammatory markers. The effect of IR should be taken into account when interpreting data of [18F]FDG uptake as a marker for AT inflammation.

scholarly journals FSMP-09. FORMATE PROMOTES CANCER CELL INVASION AND METASTASIS VIA CALCIUM SIGNALING

2020 ◽  
Vol 3 (Supplement_1) ◽  
pp. i18-i18
Author(s):  
Catherine Delbrouck ◽  
Vitaly I Pozdeev ◽  
Anais Oudin ◽  
Kamil Grzyb ◽  
Laura Neises ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Ex Vivo ◽  
Tumor Model ◽  
Underlying Mechanism ◽  
Tumor Escape ◽  
Proliferating Cells ◽  
Nucleotide Synthesis ◽  
Formate Production

Abstract Serine catabolism via the folate cycle provides formate that is essential for nucleotide synthesis in proliferating cells. In addition to this canonical function to support biomass production in anabolic cells, we have recently demonstrated in vitro and in vivo that formate production in cancer cells is often in excess of the anabolic demand. This excess formate production is characterized by formate overflow and thus, net formate excretion into the tumor microenvironment. Interestingly, we observe increased rates of formate overflow upon different chemical perturbations that induce growth arrest. Thus, stressed cancer cells that encounter growth restriction such as upon chemotherapy, are often characterized by increased formate release rates. We demonstrated that such high formate levels in the extracellular space promote invasion of glioblastoma cells. Using ex vivo brain slice cultures and an orthotopic brain tumor model, we demonstrate that silencing MTHFD1L, the essential enzyme to enable formate overflow, results in decreased invasiveness of the tumor. Embarking from this observation, we investigated the underlying mechanism and now provide evidence that the formate-dependent increase of cell motility is mediated by an activation of Ca2+ signaling. Activation of Ca2+ signaling triggers integrin and matrix metallopeptidase (MMP) responses enabling the invasion process. Targeting either the Ca2+ response or MMP release can suppress the formate dependent increase in invasion. Finally, we tested the effect of formate also in context of breast cancer where we were able to recapitulate our observation of increased invasiveness and, in this case, formate also promoted the metastatic potential. We conclude that excreted formate might serve as a cellular stress signal that represents a promotive trigger to support tumor escape mechanisms.

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