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Antibody-drug conjugates (ADCs) consist of monoclonal antibodies that target tumor cells and cytotoxic drugs linked through linkers. By leveraging antibodies' targeting properties, ADCs deliver cytotoxic drugs into tumor cells via endocytosis after identifying the tumor antigen. This precise method aims to kill tumor cells selectively while minimizing harm to normal cells, offering safe and effective therapeutic benefits. Recent years have seen significant progress in antitumor treatment with ADC development, providing patients with new and potent treatment options. With over 300 ADCs explored for various tumor indications and some already approved for clinical use, challenges such as resistance due to factors like antigen expression, ADC processing, and payload have emerged. This review aims to outline the history of ADC development, their structure, mechanism of action, recent composition advancements, target selection, completed and ongoing clinical trials, resistance mechanisms, and intervention strategies. Additionally, it will delve into the potential of ADCs with novel markers, linkers, payloads, and innovative action mechanisms to enhance cancer treatment options. The evolution of ADCs has also led to the emergence of combination therapy as a new therapeutic approach to improve drug efficacy.
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Artificially modified adsorbing materials mainly aim to remedy the disadvantages of natural materials as much as possible. Using clay materials such as rectorite, sodium bentonite and metakaolinite (solid waste material) as base materials, hydrothermally modified and unmodified materials were compared. CM-HT and CM (adsorbing materials) were prepared and used to adsorb and purify wastewater containing malachite green (MG) dye, and the two materials were characterized through methods such as BET, FT-IR, SEM and XRD. Results: (1) The optimal conditions for hydrothermal modification of CM-HT were a temperature of 150 °C, a time of 2 h, and a liquid/solid ratio 1:20. (2) Hydrothermal modification greatly increased the adsorptive effect. The measured maximum adsorption capacity of CM-HT for MG reached 290.45 mg/g (56.92% higher than that of CM). The theoretical maximum capacity was 625.15 mg/g (186.15% higher than that of CM). (3) Because Al-OH and Si-O-Al groups were reserved in unmodified clay mineral adsorbing materials with good adsorbing activity, after hydrothermal modification, the crystal structure of the clay became loosened along the direction of the c axis, and the interlayer space increased to partially exchange interlayer metal cations connected to the bottom oxygen, giving CM-HT higher electronegativity and creating more crystal defects and chemically active adsorbing sites for high-performance adsorption. (4) Chemical adsorption was the primary way by which CM-HT adsorbed cationic dye, while physical adsorption caused by developed pore canal was secondary. The adsorption reaction occurred spontaneously.
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Irradiation (IR) induces immunogenic cell death (ICD) in tumors, but it rarely leads to the abscopal effect (AE); even combining IR with immune checkpoint inhibitors has shown only anecdotal success in inducing AEs. In this study, we aimed to enhance the IR-induced immune response and generate reproducible AEs using the anti-alcoholism drug, disulfiram (DSF), complexed with copper (DSF/Cu) to induce tumor ICD. We measured ICD in vitro and in vivo. In mouse tumor models, DSF/Cu was injected intratumorally followed by localized tumor IR, creating an in situ cancer vaccine. We determined the anticancer response by primary tumor rejection and assessed systemic immune responses by tumor rechallenge and the occurrence of AEs relative to spontaneous lung metastasis. In addition, we analyzed immune cell subsets and quantified proinflammatory and immunosuppressive chemokines/cytokines in the tumor microenvironment (TME) and blood of the vaccinated mice. Immune cell depletion was investigated for its effects on the vaccine-induced anticancer response. The results showed that DSF/Cu and IR induced more potent ICD under hypoxia than normoxia in vitro. Low-dose intratumoral (i.t.) injection of DSF/Cu and IR(12Gy) demonstrated strong anti-primary and -rechallenged tumor effects and robust AEs in mouse models. These vaccinations also increased CD8+ and CD4+ cell numbers while decreasing Tregs and myeloid-derived suppressor cells in the 4T1 model, and increased CD8+, dendritic cells (DC), and decreased Treg cell numbers in the MCa-M3C model. Depleting both CD8+ and CD4+ cells abolished the vaccine's anticancer response. Moreover, vaccinated tumor-bearing mice exhibited increased TNFα levels and reduced levels of immunosuppressive chemokines/cytokines. In conclusion, our novel approach generated an anticancer immune response that results in a lack of or low tumor incidence post-rechallenge and robust AEs, i.e., absence of or decreased spontaneous lung metastasis in tumor-bearing mice. This approach is readily translatable to clinical settings and may increase IR-induced AEs in cancer patients.
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Neoplasias da Mama , Vacinas Anticâncer , Cobre , Dissulfiram , Morte Celular Imunogênica , Dissulfiram/farmacologia , Animais , Vacinas Anticâncer/farmacologia , Vacinas Anticâncer/imunologia , Feminino , Camundongos , Morte Celular Imunogênica/efeitos dos fármacos , Cobre/farmacologia , Humanos , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Microambiente Tumoral/efeitos dos fármacos , Camundongos Endogâmicos BALB CRESUMO
Irradiation (IR) induces immunogenic cell death (ICD) in tumors, but it rarely leads to the abscopal effect (AE). However, combining IR with immune checkpoint inhibitors has shown anecdotal success in inducing AEs. In this study, we aimed to enhance the IR-induced immune response and generate reproducible AEs using the anti-alcoholism drug disulfiram (DSF) and copper complex (DSF/Cu) via induction of tumor ICD. We measured ICD in vitro and in vivo. In mouse tumor models, DSF/Cu was injected intratumorally followed by localized tumor IR, creating an in situ cancer vaccine. We determined the anti-cancer response by primary tumor rejection and assessed systemic immune responses by tumor rechallenge and the occurrence of AEs, i.e., spontaneous lung metastasis. Additionally, we analyzed immune cell subsets and quantified proinflammatory and immunosuppressive chemokines/cytokines in the tumor microenvironment (TME) and blood of the vaccinated mice. Immune cell depletion was investigated for its effects on the vaccine-induced anti-cancer response. The results showed that DSF/Cu and IR induced more potent ICD under hypoxia than normoxia in vitro. Low-dose intratumoral injection of DSF/Cu and IR demonstrated strong anti-primary and -rechallenged tumor effects and robust AEs in mouse models. These vaccinations also increased CD8 + and CD4 + cell numbers while decreasing Tregs and myeloid-derived suppressor cells in the 4T1 model, and increased CD8+, DC, and decreased Treg cell numbers in the MCa-M3C model. Depleting both CD8 + and CD4 + cells abolished the vaccine's anticancer response. Moreover, vaccinated tumor-bearing mice exhibited increased TNFα levels and reduced levels of immunosuppressive chemokines/cytokines. In conclusion, our novel approach generated an anti-cancer immune response, resulting in a lack of or low tumor incidence post-rechallenge and robust AEs, i.e., the absence of or decreased spontaneous lung metastasis in tumor-bearing mice. This approach is readily translatable to clinical settings and may increase IR-induced AEs in cancer patients.
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BACKGROUND: The aim of this study was to systematically evaluate the prognostic role of platelet lymphocyte ratio (PLR) in patients with melanoma through performing a meta-analysis. METHODS: PubMed, EMBASE, Web of Science, and China National Knowledge Infrastructure were searched for potential studies. The basic characteristics and relevant data were extracted. Hazard ratios with 95% confidence intervals (CIs) were pooled to evaluate the prognostic role of PLR in patients with melanoma. RESULTS: Ten studies enrolling 2422 patients were included. The pooled hazard ratios of higher PLR for overall survival and progression-free survival in melanoma were 1.70 (95% CI, 1.22-2.37) and 1.65 (95% CI, 1.10-2.47), respectively. Sensitivity analysis and subgroup analyses were also performed. No significant publication bias was observed. CONCLUSION: Our results showed that higher PLR was associated with poorer overall survival and progression-free survival in patients with melanoma. These findings may help to determine the prognosis and explore future novel therapies based on modulating inflammation and immune responses in melanoma.
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Plaquetas , Linfócitos , Melanoma/sangue , Valor Preditivo dos Testes , Humanos , Melanoma/complicações , Melanoma/mortalidade , Modelos de Riscos ProporcionaisRESUMO
An amendment to this paper has been published and can be accessed via the original article.
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BACKGROUND: The current successful clinical use of agents promoting robust anti-tumor immunity in cancer patients warrants noting that radiation therapy (RT) induces immunogenic cell death (ICD) of tumor cells, which can generate anti-tumor immune responses. However, breast cancer stem cells (BCSCs) are resistant to RT and RT alone usually failed to mount an anti-tumor immune response. METHODS: High aldehyde dehydrogenase activity (ALDH)bright and CD44+/CD24-/ESA+ cancer cells, previously shown to have BCSC properties, were isolated from human MDA-MB-231 and UACC-812 breast cancer cell lines by flow cytometer. Flow sorted BCSCs and non-BCSCs were further tested for their characteristic of stemness by mammosphere formation assay. Induction of ICD in BCSCs vs. non-BCSCs in response to different in vitro treatments was determined by assessing cell apoptosis and a panel of damage-associated molecular pattern molecules (DAMPs) by flow and enzyme-linked immunosorbent assay (ELISA). RESULTS: We found that ionizing radiation (IR) triggered a lower level of ICD in BCSCs than non-BCSCs. We then investigated the ability of disulfiram/cooper (DSF/Cu) which is known to preferentially induce cancer stem cells (CSCs) apoptosis to enhance IR-induced ICD of BCSCs. The results indicate that DSF/Cu induced a similar extent of IDC in both BCSCs and non-BCSCs and rendered IR-resistant BCSCs as sensitive as non-BCSCs to IR-induced ICD. IR and DSF/Cu induced ICD of BCSCs could be partly reversed by pre-treatment of BCSCs with a reactive oxygen species (ROS) scavenger and XBP1s inhibitors. CONCLUSION: DSF/Cu rendered IR-resistant BCSCs as sensitive as non-BCSCs to IR-induced ICD. Our data demonstrate the potential of IR and DSF/Cu to induce ICD in BCSCs and non-BCSCs leading to robust immune responses against not only differentiated/differentiating breast cancer cells but also BCSCs, the root cause of cancer formation, progression and metastasis.
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Antineoplásicos , Neoplasias da Mama/tratamento farmacológico , Dissulfiram , Reposicionamento de Medicamentos , Morte Celular Imunogênica/efeitos dos fármacos , Tolerância a Radiação/efeitos dos fármacos , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Neoplasias da Mama/patologia , Neoplasias da Mama/radioterapia , Linhagem Celular Tumoral , Dissulfiram/administração & dosagem , Dissulfiram/farmacologia , Feminino , Humanos , Células-Tronco NeoplásicasRESUMO
BACKGROUND: Despite therapeutic advancements (e.g. B-RAF inhibitors) targeting cutaneous melanoma, many cellular processes, including inducible heme oxygenase 1 (HO-1), counteract treatments for malignancies. So there is an urgent need to find biological treatment targets, develop new therapeutic approaches and achieve longer responses. This study aimed to explore the relationship of HO-1 and B-Raf via mediating ERK1/2 signaling on cell cycle in melanoma. METHODS: Immunohistochemistry was applied to evaluate the levels of HO-1 and B-Raf expression in melanoma tissues and adjacent healthy tissues. Co-immunoprecipitation (Co-IP) assessed the interaction of HO-1 with B-Raf. Further study overexpression and knock-down of HO-1 in A375 cell lines, especially knockout HO-1 using CRISPR-Cas9, verified HO-1 regulate cell proliferation in vivo and in vitro. Finally, Western blot analysis and qRT-PCR were performed to investigate the mechanisms by which HO-1 mediates cell cycle by B-RAF-ERK1/2 signaling. RESULTS: First, histology and Co-IP show that HO-1 interacts with B-Raf directly in melanoma tissue. Further study illustrated that HO-1 overexpression promotes melanoma cell proliferation while HO-1 reduction represses melanoma cell proliferation because of HO-1 affects cell cycle. Mechanistic studies revealed that HO-1 was associated with a marked activation of B-RAF-ERK1/2 signaling and led to CDK2/cyclin E activation, thereby promoting melanoma proliferation. CONCLUSIONS: Our result reveals a previously unknown mechanism that the HO-1-B-RAF-ERK axis plays an important role in melanoma cell proliferation. Therapeutic target on HO-1 could be a novel method for treating melanoma.
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Heme Oxigenase-1/metabolismo , Sistema de Sinalização das MAP Quinases , Melanoma/metabolismo , Melanoma/patologia , Proteínas Proto-Oncogênicas B-raf/metabolismo , Animais , Sequência de Bases , Ciclo Celular , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Camundongos Nus , Fosforilação , Ligação ProteicaRESUMO
@# Objective: To explore the effect of shRNA interfering BAMBI (bone morphogenetic protein and activin membrane bound inhibitor) on the proliferation, apoptosis, invasion and migration of human colon cancer SW480 cells and the possible mechanisms. Methods: After successful transfection with sh-BAMBI in SW480 cells, the mRNA and protein epxressions of BAMBI were detected by qRT-PCR and Western blotting, respectively. Cell proliferation was measured by MTT; apoptosis was tested by Hoechst33258 staining; cell invasion was detected by transwell assay; and cell migration was measured by wound healing assay. The expressions of TGF-β/ Smad/2 signaling pathway related proteins were detected by Western blotting. Results: The mRNA and protein levels of BAMBI in shBAMBI group were lower than those of control group (P<0.05). Compared with control group, cell proliferation in sh-BAMBI group was obviously decreased (P<0.05), while apoptosis was obviously increased (P<0.01); in the meanwhile, cell invasion and migration in sh-BAMBI group were significantly reduced (P<0.05). In addition, the protein level of TGF-β and the ratio of p-Smad/2/ Smad/2 in shBAMBI group were significantly higher than those in control group (P<0.05). Conclusion: Interference of BAMBI by shRNA inhibits proliferation, invasion and migration but induces apoptosis of human colon cancer SW480 cells and activates TGF-β/Smad/2 pathway.
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Melanoma, as one of the most highly metastatic types of cancer, is resistant to current treatment methods, including popular targeted molecular therapy. Consequently, it is essential to develop a deeper understanding of the mechanisms involved in melanoma progression so that alternative treatments may be identified. To date, accumulating evidence supports the use of calpains, including calpain small subunit 1 (also known as Capn4 or CAPNS1), which affect cancer progression through many pathways, such as epithelialmesenchymal transition (EMT), the Wnt/ß-catenin (ß-catenin) and the nuclear factor κB (NF-κB) signaling pathways. The EMT pathway is well known as one of the most important events in tumor metastasis. The present study observed cross-talk among the EMT, ß-catenin and NF-κB pathways. To identify the underlying mechanisms of Capn4 activity in melanoma cells, we determined Capn4 expression by gene chip and immunohistochemistral analyses in melanoma tissues and cells in vitro. The extent of apoptosis as determined by TUNEL assay, DAPI staining, and cleaved-caspase-3 assay was increased in human melanoma cells in which Capn4 expression had been knocked down when compared with untreated cells. Transwell assays and xenograft tumorigenicity studies were also performed to assess the effects of Capn4 on migration and invasion in vitro and tumor growth in vivo, respectively. The levels of ß-catenin, vimentin, E-cadherin and N-cadherin were altered in human melanoma cells as determined by western blot analysis assay. Our study demonstrated that Capn4 is an underlying target for melanoma treatment.
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Calpaína/metabolismo , Transição Epitelial-Mesenquimal , Melanoma/metabolismo , Melanoma/patologia , Via de Sinalização Wnt , beta Catenina/metabolismo , Animais , Calpaína/genética , Caspase 3/metabolismo , Linhagem Celular Tumoral , Movimento Celular/genética , Humanos , Camundongos Endogâmicos BALB C , NF-kappa B/metabolismo , RNA Interferente Pequeno , Transdução de Sinais , Transfecção , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Specificity protein1 (Sp1) is required for TGF-ß-induced epithelial-to-mesenchymal transition (EMT) which has been demonstrated to aggravate the progression of cancer including lung cancer. microRNA-29c (miR-29c) is identified to inhibit EMT, but the correlation between miR-29c and Sp1 in human lung cancer remain incompletely clarified. Here, we confirmed decreased expression of miR-29c and enhanced expression of Sp1 in lung cancer tissues (n = 20) and found that Sp1 could be targeted and inhibited by miR-29c. Besides, the expression of miR-29c was down-regulated in high-metastatic lung cancer cell lines and TGF-ß1-treated cells. The inhibition of miR-29c or overexpression of Sp1 in 95C and A549 cells dramatically enhanced the cell migration and invasion, and also induced the decrease in the expression of epithelial markers, e.g. thyroid transcription factor 1 (TTF-1) and E-cadherin, together with an increase in mesenchymal markers including vimentin, α-smooth muscle actin (α-SMA), which could be restored by overexpression of miR-29c mimics during the TGF-ß-induced EMT. Moreover, dual-luciferase reporter assay was performed and the results indicated that miR-29c/Sp1 could form an auto-regulatory loop with TGF-ß1, which impaired TGFB1 transcription. Furthermore, miR-29c overexpression could abrogate the tumor progression and inhibit the Sp1/TGF-ß expressions in vivo, indicating that miR-29c could be a tumor suppressor and repress the Sp1/TGF-ß axis-induced EMT in lung cancer.
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Neoplasias Pulmonares/patologia , MicroRNAs/fisiologia , Fator de Transcrição Sp1/fisiologia , Fator de Crescimento Transformador beta1/fisiologia , Animais , Linhagem Celular Tumoral , Movimento Celular , Transição Epitelial-Mesenquimal , Humanos , Camundongos , Invasividade NeoplásicaRESUMO
A mineral-based porous granulation material (MPGM) was prepared for absorbing the heavy metal ions from quartz processing wastewater. Analytic results of the MPGM were illustrated by the techniques of BET, SEM and FT-IR, which revealed the excellent properties of multi-aperture distribution, large specific surface area, low loss ratio and so on; the N2 adsorption-desorption isotherm was type-III with H4 hysteresis loop; the functional groups were dominated by groups of layer silicate mineral. A batch adsorption study was carried out with varied adsorbent dosage, initial pH and reaction time. The results showed that the residual ion concentrations of Fe, Zn, Mn and As were decreased from 77.760, 3.700, 2.789 and 0.963 mg x L(-1) to 3.421, 0.574, 0.126 and 0.034 mg x L(-1), respectively. MPGM might be re-utilized after desorption by 1.0 mol x L(-1) NaCl for 12 hours, and the ideal adsorption performance was maintained after 5 recyclings. The adsorption equilibrium and kinetics followed Langmuir and typical pseudo-first-order/pseudo-second-order adsorption models. Thermodynamic parameters of ΔG(θ) < 0, ΔHθ > 0, ΔSθ > 0 showed that the adsorptions were spontaneous and endothermic processes in the temperature range of 15-45 degrees C.