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1.
Sci Rep ; 14(1): 15682, 2024 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-38977778

RESUMO

This study constructed a comprehensive analysis of cell death modules in eliminating aberrant cells and remodeling tumor microenvironment (TME). Consensus analysis was performed in 490 lung adenocarcinoma (LUAD) patients based on 4 types of cell death prognostic genes. Intersection method divided these LUAD samples into 5 cell death risk (CDR) clusters, and COX regression analysis were used to construct the CDR signature (CDRSig) with risk scores. Significant differences of TME phenotypes, clinical factors, genome variations, radiosensitivity and immunotherapy sensitivity were observed in different CDR clusters. Patients with higher risk scores in the CDRSig tended to be immune-excluded or immune-desert, and those with lower risk scores were more sensitive to radiotherapy and immunotherapy. The results from mouse model showed that intense expression of the high-risk gene PFKP was associated with low CD8+ T cell infiltration upon radiotherapy and anti-PD-L1 treatment. Deficient assays in vitro confirmed that PFKP downregulation enhanced cGAS/STING pathway activation and radiosensitivity in LUAD cells. In conclusion, our studies originally performed a comprehensive cell death analysis, suggesting the importance of CDR patterns in reprogramming TME and providing novel clues for LUAD personalized therapies.


Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Medicina de Precisão , Microambiente Tumoral , Microambiente Tumoral/imunologia , Humanos , Adenocarcinoma de Pulmão/imunologia , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/terapia , Adenocarcinoma de Pulmão/patologia , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/patologia , Medicina de Precisão/métodos , Animais , Camundongos , Morte Celular , Regulação Neoplásica da Expressão Gênica , Imunoterapia/métodos , Linhagem Celular Tumoral , Prognóstico , Feminino , Masculino
2.
Nat Med ; 2024 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-38992123

RESUMO

Immunochemotherapy is the first-line standard for extensive-stage small-cell lung cancer (ES-SCLC). Combining the regimen with anti-angiogenesis may improve efficacy. ETER701 was a multicenter, double-blind, randomized, placebo-controlled phase 3 trial that investigated the efficacy and safety of benmelstobart (a novel programmed death-ligand 1 (PD-L1) inhibitor) with anlotinib (a multi-target anti-angiogenic small molecule) and standard chemotherapy in treatment-naive ES-SCLC. The ETER701 trial assessed two primary endpoints: Independent Review Committee-assessed progression-free survival per RECIST 1.1 and overall survival (OS). Here the prespecified final progression-free survival and interim OS analysis is reported. Patients randomly received benmelstobart and anlotinib plus etoposide/carboplatin (EC; n = 246), placebo and anlotinib plus EC (n = 245) or double placebo plus EC ('EC alone'; n = 247), followed by matching maintenance therapy. Compared with EC alone, median OS was prolonged with benmelstobart and anlotinib plus EC (19.3 versus 11.9 months; hazard ratio 0.61; P = 0.0002), while improvement of OS was not statistically significant with anlotinib plus EC (13.3 versus 11.9 months; hazard ratio 0.86; P = 0.1723). The incidence of grade 3 or higher treatment-related adverse events was 93.1%, 94.3% and 87.0% in the benmelstobart and anlotinib plus EC, anlotinib plus EC, and EC alone groups, respectively. This study of immunochemotherapy plus multi-target anti-angiogenesis as first-line treatment achieved a median OS greater than recorded in prior randomized studies in patients with ES-SCLC. The safety profile was assessed as tolerable and manageable. Our findings suggest that the addition of anti-angiogenesis therapy to immunochemotherapy may represent an efficacious and safe approach to the management of ES-SCLC. ClinicalTrials.gov identifier: NCT04234607 .

3.
Med ; 2024 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-38964333

RESUMO

BACKGROUND: Immune checkpoint inhibitors (ICIs) provide modest but unsatisfactory benefits for extensive-stage small cell lung cancer (ES-SCLC). Developing strategies for treating ES-SCLC is critical. METHODS: We preliminarily explored the outcomes of salvage low-dose radiotherapy (LDRT) plus ICI on refractory SCLC patients. Next, we evaluated the combinational efficacy in murine SCLC. The tumor immune microenvironment (TIME) was analyzed for mechanistic study. Subsequently, we conducted a multicenter, prospective phase II trial that administered concurrent thoracic LDRT plus chemoimmunotherapy to treatment-naive ES-SCLC patients (MATCH trial, NCT04622228). The primary endpoint was confirmed objective response rate (ORR), and the key secondary endpoints included progression-free survival (PFS) and safety. FINDINGS: Fifteen refractory SCLC patients treated with LDRT plus ICI were retrospectively reviewed. The ORR was 73.3% (95% confidence interval [CI], 44.9-92.2). We identified a specific dose of LDRT (15 Gy/5 fractions) that exhibited growth retardation and improved survival in murine SCLC when combined with ICIs. This combination recruited a special T cell population, TCF1+ PD-1+ CD8+ stem-like T cells, from tumor-draining lymph nodes into the TIME. The MATCH trial showed a confirmed ORR of 87.5% (95% CI, 75.9-94.8). The median PFS was 6.9 months (95% CI, 5.4-9.3). CONCLUSIONS: These findings verified that LDRT plus chemoimmunotherapy was safe, feasible, and effective for ES-SCLC, warranting further investigation. FUNDING: This research was funded by West China Hospital (no. ZYJC21003), the National Natural Science Foundation of China (no. 82073336), and the MATCH trial was fully funded by Roche (China) Holding Ltd. (RCHL) and Shanghai Roche Pharmaceuticals Ltd. (SRPL).

4.
Brachytherapy ; 2024 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-38960768

RESUMO

BACKGROUND AND PURPOSE: 3D-printed templates are used in intracavitary/interstitial brachytherapy (3DP-IC/IS) for locally advanced cervical cancer (LACC). We applied failure mode and effects analysis (FMEA) twice in one year to improve 3DP-IC/IS safety. MATERIALS AND METHODS: A risk assessment group was established. We created a process map for 3DP-IC/IS procedures, identifying potential failure modes (FMs) and evaluating occurrence (O), detectability (D), severity (S), and risk priority number (RPN = O*D*S). High RPN values identified high-risk FMs, and quality control (QC) methods were determined by root cause analysis. A second FMEA was performed a year later. RESULTS: The 3DP-IC/IS process included 10 main steps, 48 subprocesses, and 54 FMs. Initial RPN values ranged from 4.50 to 171.00 (median 50.50; average 52.18). Ten high-risk FMs were identified: (1) unreasonable needle track design (171.00/85.50), (2) noncoplanar needle label identification failure (126.00/64.00), (3) template model reconstruction failure (121.50/62.50), (4) improper gauze filling (112.00/60.25), (5) poor needle position (112.00/52.50). QC interventions lowered all high-risk RPN values during the second assessment. CONCLUSIONS: A feasible 3DP-IC/IS process was proposed. Staff training, automatic needle path planning, insertion guidance diagrams, template checking, system commissioning, and template design improvements effectively enhanced process safety.

5.
Cancer Immunol Immunother ; 73(4): 71, 2024 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-38430394

RESUMO

BACKGROUND: Due to individual differences in tumors and immune systems, the response rate to immunotherapy is low in lung adenocarcinoma (LUAD) patients. Combinations with other therapeutic strategies improve the efficacy of immunotherapy in LUAD patients. Although radioimmunotherapy has been demonstrated to effectively suppress tumors, the underlying mechanisms still need to be investigated. METHODS: Total RNA from LUAD cells was sequenced before and after radiotherapy to identify differentially expressed radiation-associated genes. The similarity network fusion (SNF) algorithm was applied for molecular classification based on radiation-related genes, immune-related genes, methylation data, and somatic mutation data. The changes in gene expression, prognosis, immune cell infiltration, radiosensitivity, chemosensitivity, and sensitivity to immunotherapy were assessed for each subtype. RESULTS: We used the SNF algorithm and multi-omics data to divide TCGA-LUAD patients into three subtypes. Patients with the CS3 subtype had the best prognosis, while those with the CS1 and CS2 subtypes had poorer prognoses. Among the strains tested, CS2 exhibited the most elevated immune cell infiltration and expression of immune checkpoint genes, while CS1 exhibited the least. Patients in the CS2 subgroup were more likely to respond to PD-1 immunotherapy. The CS2 patients were most sensitive to docetaxel and cisplatin, while the CS1 patients were most sensitive to paclitaxel. Experimental validation of signature genes in the CS2 subtype showed that inhibiting the expression of RHCG and TRPA1 could enhance the sensitivity of lung cancer cells to radiation. CONCLUSIONS: In summary, this study identified a risk classifier based on multi-omics data that can guide treatment selection for LUAD patients.


Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Humanos , Multiômica , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/terapia , Imunoterapia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Análise por Conglomerados , Prognóstico
6.
Int J Nanomedicine ; 19: 403-414, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38250189

RESUMO

Background: Radiotherapy is an indispensable part of the multidisciplinary treatment of breast cancer (BC). Due to the potential for serious side effects from ionizing radiation in the treatment of breast cancer, which can adversely affect the patient's quality of life, the radiation dose is often limited. This limitation can result in an incomplete eradication of tumors. Methods: In this study, biomimetic copper single-atom catalysts (platelet cell membrane camouflaging, PC) were synthesized with the aim of improving the therapeutic outcomes of radiotherapy for BC. Following guidance to the tumor site facilitated by the platelet cell membrane coating, PC releases a copper single-atom nanozyme (SAzyme). This SAzyme enhances therapeutic effects by generating reactive oxygen species from H2O2 and concurrently inhibiting the self-repair mechanisms of cancer cells through the consumption of intracellular glutathione (GSH) within the tumor microenvironment. PC-augmented radiotherapy induces immunogenic cell death, which triggers an immune response to eradicate tumors. Results: With the excellent biocompatibility, PC exhibited precise tumor-targeting capabilities. Furthermore, when employed in conjunction with radiotherapy, PC showed impressive tumor elimination results through immunological activation. Remarkably, the tumor suppression rate achieved with PC-enhanced radiotherapy reached an impressive 93.6%. Conclusion: Therefore, PC presents an innovative approach for designing radiosensitizers with tumor-specific targeting capabilities, aiming to enhance the therapeutic impact of radiotherapy on BC.


Assuntos
Neoplasias da Mama , Radioimunoterapia , Humanos , Feminino , Cobre/farmacologia , Peróxido de Hidrogênio , Qualidade de Vida , Neoplasias da Mama/radioterapia , Glutationa , Microambiente Tumoral
7.
Front Oncol ; 13: 1265749, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38074661

RESUMO

Background: Poorly differentiated non-small cell lung cancer (NSCLC) is characteristic of high rate of distant metastasis and late stages at diagnosis. Small intestine metastasis is a rare but severe complication of lung cancer with a high rate of mortality. However, there is currently a lack of genetic profile studies on the small intestine metastasis of lung cancer. Case presentations: We present 2 cases of male patients in their 60s with primary NSCLC of low differentiation, initially with no distant metastasis detected. Biopsy samples were obtained from the primary pulmonary lesions, and both patients received systematic radiotherapy (RT) and chemotherapy. However, both cases presented with abdominal pain and distension, and immunohistochemistry of small intestine biopsy samples obtained by endoscopy confirmed lung cancer metastasis. Next generation sequencing was used to explore the genetic profiles from the biopsy samples of both the primary pulmonary lesions and small intestine metastases. The correlated genes responsible for the small intestine metastasis from poorly differentiated NSCLC in these 2 patients included TP53, LRP1B, and FGFR2. The reports of small intestine metastasis from poorly differentiated NSCLC with the past 5 years were systematically reviewed and summarized subsequently. Conclusions: Poorly differentiated NSCLC with small intestine metastases, while rare, substantially impacts the prognosis and poses major challenges for diagnosis and treatment. Through comparisons of genetic profiles between patients and in the same patient before and after metastasis, we identified the mutations in genes such as TP53, LRP1B, and FGFR2, which were correlated with the occurrence and progression of poorly differentiated NSCLC, as well as its small intestinal metastasis. This discovery has the potential to guide clinicians in developing personalized treatment plans through the manipulation of targeted and radiation therapies.

8.
Genet Test Mol Biomarkers ; 27(12): 393-405, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38156905

RESUMO

Background: There is increasing evidence that abnormal expression of microRNAs is involved in the occurrence and progression of tumors. In previous experiments, we found that the content of hsa-miR-1301-3p in tumor tissues of patients with nonsmall cell lung cancer (NSCLC) showed an obvious upward trend compared with that in normal tissues. We performed a detailed study on the impact and underlying mechanism of hsa-miR-1301-3p in NSCLC cells. Methods: The impact of hsa-miR-1301-3p on NSCLC cell proliferation, apoptosis, migration, and invasion was examined using colony formation, flow cytometry, modified Boyden chamber, and wound healing assays. Different doses of radiation were applied to NSCLC cells to investigate their sensitivity to radiotherapy. The potential target gene of hsa-miR-1301-3p was determined by dual-luciferase reporter assay and immunoblotting. Result: hsa-miR-1301-3p was upregulated in NSCLC tissues and cells. hsa-miR-1301-3p effectively promoted the rapid proliferation, migration, and invasion of NSCLC cells, while inhibiting apoptosis. It also induced radioresistance in NSCLC cells. hsa-miR-1301-3p targeted the homeodomain-only protein homeobox (HOPX) mRNA 3' untranslated region and inhibited its transcription in NSCLC cells. Exogenous HOPX overexpression antagonized the mechanism by which hsa-miR-1301-3p regulates NSCLC cell proliferation, metastasis, and apoptosis. Conclusions: hsa-miR-1301-3p plays an oncogenic role in the occurrence and development of NSCLC. By targeting HOPX, hsa-miR-1301-3p can not only promote the proliferation and metastasis of NSCLC cells, but also alleviate apoptosis and reduce radiosensitivity.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , MicroRNAs , Humanos , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Genes Homeobox , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/radioterapia , Neoplasias Pulmonares/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Tolerância a Radiação/genética
9.
BMC Cancer ; 23(1): 1168, 2023 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-38031013

RESUMO

BACKGROUND: Prophylactic irradiation of supraclavicular lymph node drainage areas can improve the regional control rate of lymph node-positive or lymph node-negative disease but a locally-advanced stage breast cancer, and it can reduce breast cancer-related mortality. However, many controversies exist in the clinical target volume delineation of supraclavicular lymph node drainage in patients with breast cancer. METHODS: We retrospectively analyzed 42 patients with breast cancer and supraclavicular lymph node metastasis at our hospital between January 2017 and December 2021. Among these cases, 32 were locally advanced and 10 were stage IV at initial treatment. A patient with breast cancer who did not undergo dissection of the supraclavicular and infraclavicular lymph nodes at our hospital was selected as a standard patient. A contrast-enhanced computed tomography (CT) scan for positioning was used as a template image, and blood vessels, muscles, and bony landmarks were used as references for positioning. The metastatic supraclavicular lymph nodes were identified in all enrolled patients and projected into the template CT images. RESULTS: The metastastic pattern of supraclavicular lymph node in breast cancer was proposed: distribution along the posterolateral border of the internal jugular vein (medial supraclavicular group) and along the transverse jugular vein (lateral supraclavicular group). We theorized that the lateral and posterior borders of the clinical target volume in the supraclavicular region should include the lymph nodes in the posterior triangle of the neck (level V) in high-risk individuals. If the metastatic axillary lymph node is extensive, then the superior border of the supraclavicular region should be moved upward appropriately. CONCLUSIONS: This study analyzed patients with breast cancer and supraclavicular lymph node metastasis at initial treatment, explored the metastastic pattern of supraclavicular lymph node, and applied anatomical knowledge to further optimize the target volume delineation of supraclavicular lymph node drainage area in high-risk breast cancer.


Assuntos
Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/patologia , Metástase Linfática/patologia , Estudos Retrospectivos , Linfonodos/diagnóstico por imagem , Linfonodos/patologia , Mama/patologia , Axila/patologia , Excisão de Linfonodo
10.
Eur J Med Res ; 28(1): 463, 2023 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-37884978

RESUMO

BACKGROUND: A novel CT-linac (kilovolt fan-beam CT-linac) has been introduced into total marrow and lymphoid irradiation (TMLI) treatment. Its integrated kilovolt fan-beam CT (kV FBCT) can be used not only for image guidance (IGRT) but also to re-calculate the dose. PURPOSE: This study reported our clinical routine on performing TMIL treatment on the CT-linac, as well as dose distribution comparison between planned and re-calculated based on IGRT FBCT image sets. METHODS: 11 sets of data from 5 male and 6 female patients who had underwent the TMLI treatment with uRT-linac 506c were selected for this study. The planning target volumes consist of all skeletal bones exclusion of the mandible and lymphatic sanctuary sites. A planned dose of 10 Gy was prescribed to all skeletal bones exclusion of the mandible in two fractions and 12 Gy in two fractions was prescribed to lymphatic sanctuary sites. Each TMLI plan contained two sub-plans, one dynamic IMRT for the upper body and the other VMAT for the lower extremity. Two attempts were made to obtain homogeneous dose in the overlapping region, i.e., applying two plans with different isocenters for the treatment of two fractions, and using a dose gradient matching scheme. The CT scans, including planning CT and IGRT FBCT, were stitched to a whole body CT scan for dose distribution evaluation. RESULTS: The average beam-on time of Planupper is 30.6 min, ranging from 24.9 to 37.5 min, and the average beam-on time of Planlower is 6.3 min, ranging from 5.7 to 8.2 min. For the planned dose distribution, the 94.79% of the PTVbone is covered by the prescription dose of 10 Gy (V10), and the 94.68% of the PTVlymph is covered by the prescription dose of 12 Gy (V12). For the re-calculated dose distribution, the 92.17% of the PTVbone is covered by the prescription dose of 10 Gy (V10), and the 90.07% of the PTVlymph is covered by the prescription dose of 12 Gy (V12). The results showed that there is a significant difference (p < 0.05) between planning V10, V12 and delivery V10, V12. There is no significant difference (p > 0.05) between planned dose and re-calculated dose on selected organs, except for right lens (p < 0.05, Dmax). The actual delivered maximum dose of right lens is apparently larger than the planned dose of it. CONCLUSION: TMLI treatment can be performed on the CT-linac with clinical acceptable quality and high efficiency. Evaluation of the recalculated dose on IGRT FBCT suggests the treatment was delivered with adequate target coverage.


Assuntos
Radioterapia de Intensidade Modulada , Humanos , Masculino , Feminino , Radioterapia de Intensidade Modulada/efeitos adversos , Radioterapia de Intensidade Modulada/métodos , Medula Óssea , Dosagem Radioterapêutica , Planejamento da Radioterapia Assistida por Computador/métodos , Irradiação Linfática , Tomografia Computadorizada por Raios X/métodos
11.
Int J Biol Macromol ; 251: 126222, 2023 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-37586625

RESUMO

This study demonstrates that the purified ß-glucan (LNT) with a triple helix and relatively narrow molecular weight distribution, extracted and purified from artificially cultured Lentinus edodes, showed a significant cervical cancer inhibition with little cytotoxicity against normal cells in vitro and in vivo. From the in vitro data, the potential mechanism of anti-cervical cancer was preliminarily revealed as follows: LNT was firstly recognized by the human cervical cancer cell line of Hela and induced cell proliferation inhibition through p21 and apoptosis via a mitochondrion-dependent pathway by targeting the tumor suppressor of p53, indicated by an increase in reactive oxygen species (ROS) generation and a loss of mitochondrial membrane potential (Δψm), in a significant dosage-dependent manner. Meanwhile, LNT repressed tumor growth with an inhibition ratio of 61.2 % and induced tumor cell apoptosis through endogenous MDM2/p53/Bax/mitochondrion signal pathway by up-regulating the expression of p53, Bax, Cyt. c, caspase 9, and caspase 3, as well as down-regulating Bcl-2, MDM2, and PARP1 levels in Hela cells-transplanted BALB/c nude mice. This study provides a scientific basis for the clinical treatment of cervical cancer with LNT as a potential drug candidate characterized by the triple helix and specified molecular weight with a relatively narrow distribution.

12.
Immunotherapy ; 15(15): 1239-1247, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37491886

RESUMO

The prognosis for patients with distant-organ metastatic cervical cancer (CC) is poor owing to the lack of effective treatment modalities. We present a case of CC with lung metastasis that achieved partial remission of the cervical mass after two cycles of chemotherapy, while the pulmonary nodules remained stable. Moreover, the level of the tumor marker squamous cell carcinoma antigen was slightly higher than before. The patient was recommended to receive pelvic concurrent chemoradiotherapy combined with camrelizumab. Remarkably, after undergoing 16 cycles of immunotherapy, the patient's primary cervical mass and pulmonary nodules were in complete remission, and the tumor marker had returned to normal levels. This inspiring case demonstrates that a combination of chemo-/radio-/immunotherapy can be effective in treating lung metastatic CC and can also enhance the abscopal effect.


Checkpoint inhibitors are a type of treatment for cancer. They can be used alone or together with chemotherapy, and they have recently been approved for the treatment of advanced and recurrent cervical cancer. This article looks at how these checkpoint inhibitors can be used with another treatment called chemoradiotherapy. This treatment combines chemotherapy and radiation therapy. This is to see whether using checkpoint inhibitors with chemoradiotherapy can help even more. Here we report a patient with cervical cancer that had spread to the lungs. They received treatment with chemotherapy, radiation therapy and checkpoint inhibitors. The good news is that the cancer went away completely after this treatment. The patient continued to receive checkpoint inhibitors to keep the cancer from coming back. It has been 26 months, and the patient is still cancer-free. This case shows that using checkpoint inhibitors with chemoradiotherapy can be a very effective treatment for cervical cancer that has spread to other parts of the body.


Assuntos
Neoplasias Pulmonares , Neoplasias do Colo do Útero , Feminino , Humanos , Neoplasias do Colo do Útero/tratamento farmacológico , Quimiorradioterapia , Resultado do Tratamento , Prognóstico , Neoplasias Pulmonares/tratamento farmacológico , Imunoterapia
13.
Anal Chem ; 95(28): 10588-10594, 2023 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-37402148

RESUMO

N6-Methyladenosine (m6A) is one of the most abundant and prevalent natural modifications occurring in diverse RNA species. m6A plays a wide range of roles in physiological and pathological processes. Revealing the functions of m6A relies on the faithful detection of individual m6A sites in RNA. However, developing a simple method for the single-base resolution detection of m6A is still a challenging task. Herein, we report an adenosine deamination sequencing (AD-seq) technique for the facile detection of m6A in RNA at single-base resolution. The AD-seq approach capitalizes on the selective deamination of adenosine, but not m6A, by the evolved tRNA adenosine deaminase (TadA) variant of TadA8e or the dimer protein of TadA-TadA8e. In AD-seq, adenosine is deaminated by TadA8e or TadA-TadA8e to form inosine, which pairs with cytidine and is read as guanosine in sequencing. m6A resists deamination due to the interference of the methyl group at the N6 position of adenosine. Thus, the m6A base pairs with thymine and is still read as adenosine in sequencing. The differential readouts from A and m6A in sequencing can achieve the single-base resolution detection of m6A in RNA. Application of the proposed AD-seq successfully identified individual m6A sites in Escherichia coli 23S rRNA. Taken together, the proposed AD-seq allows simple and cost-effective detection of m6A at single-base resolution in RNA, which provides a valuable tool to decipher the functions of m6A in RNA.


Assuntos
RNA de Transferência , RNA , RNA/metabolismo , Desaminação , RNA de Transferência/metabolismo , Adenosina/metabolismo , Adenosina Desaminase/metabolismo
14.
Carbohydr Polym ; 316: 121069, 2023 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-37321711

RESUMO

Colorectal cancer is the third most common cancer in the world, and therapies with safety are in great need. In this study, the ß-glucan isolated from Lentinus edodes was successfully fractionated into three fractions with different weight-average molecular weight (Mw) by ultrasonic degradation and used for the treatment of colorectal cancer. In our findings, the ß-glucan was successfully degraded with the Mw decreased from 2.56 × 106 Da to 1.41 × 106 Da, exhibiting the triple helix structure without conformation disruption. The in vitro results indicate that ß-glucan fractions inhibited colon cancer cell proliferation, induced colon cancer cell apoptosis, and reduced inflammation. The in vivo results based on Azoxymethane (AOM)/dextran sulfate sodium (DSS) mouse model demonstrate that the lower-molecular weight ß-glucan fraction showed stronger anti-inflammatory and anti-colon cancer activities by reconstructing intestinal mucosal barrier, increasing short chain fatty acids (SCFAs) content, regulating metabolism of gut microbiota, and rebuilding the gut microbiota structure with the increased Bacteroides and the decreased Proteobacteria at the phylum level, as well as with the decreased Helicobacter and the increased Muribaculum at the genus level. These findings provide scientific basis for using the ß-glucan to regulate gut microbiota as an alternative strategy in the clinical treatment of colon cancer.


Assuntos
Neoplasias Associadas a Colite , Colite , Neoplasias do Colo , Microbioma Gastrointestinal , Cogumelos Shiitake , beta-Glucanas , Animais , Camundongos , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/metabolismo , beta-Glucanas/farmacologia , beta-Glucanas/uso terapêutico
15.
Lancet Respir Med ; 11(10): 905-915, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37244266

RESUMO

BACKGROUND: Befotertinib (D-0316) is a novel, selective oral third-generation epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitor. This phase 3 trial compared the efficacy and safety of befotertinib with icotinib as a first-line treatment for patients with EGFR mutation-positive locally advanced or metastatic non-small-cell lung cancer (NSCLC). METHODS: This study was a multicentre, open-label, randomised, controlled phase 3 study at 39 hospitals in China. Eligible patients were 18 years of age or older, had histologically confirmed locally advanced or metastatic stage IIIB, IIIC, or IV unresectable NSCLC, and had confirmed exon 19 deletions or exon 21 Leu858Arg mutation. Patients were randomly assigned (1:1) via an interactive web response system to receive either oral befotertinib (75-100 mg once daily) or oral icotinib (125 mg three times per day) in 21-day cycles until disease progression or withdrawal criteria were met. Randomisation was stratified by type of EGFR mutation, CNS metastasis status, and gender, and participants, investigators, and data analysts were not masked to treatment allocation. The primary endpoint was independent review committee (IRC)-assessed progression-free survival in the full analysis set, which comprised all randomly assigned patients. All patients who received at least one dose of the study drug were included in safety analyses. This study was registered with ClinicalTrials.gov, NCT04206072, and the overall survival follow-up is still in progress. FINDINGS: Between Dec 24, 2019, and Dec 18, 2020, 568 patients were screened, of whom 362 were randomly assigned to the befotertinib (n=182) or icotinib (n=180) group; all 362 patients were included in the full analysis set. Median follow-up was 20·7 months (IQR 10·2-23·5) in the befotertinib group and 19·4 months (10·3-23·5) in the icotinib group. Median IRC-assessed progression-free survival was 22·1 months (95% CI 17·9-not estimable) in the befotertinib group and 13·8 months (12·4-15·2) in the icotinib group (hazard ratio 0·49 [95% CI 0·36-0·68], p<0·0001). Grade 3 or higher treatment-related adverse events occurred in 55 (30%) of 182 patients in the befotertinib group and in 14 (8%) of 180 patients in the icotinib group. Treatment-related serious adverse events were reported in 37 (20%) patients in the befotertinib group and in five (3%) patients in the icotinib group. Two (1%) patients in the befotertinib group and one (1%) patient in the icotinib group died due to treatment-related adverse events. INTERPRETATION: Befotertinib demonstrated superior efficacy compared with icotinib in first-line treatment for patients with EGFR mutation-positive NSCLC. Although serious adverse events were more common in the befotertinib than the icotinib arm, the safety profile of befotertinib was manageable overall. FUNDING: Betta Pharmaceuticals (China). TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Adolescente , Adulto , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Intervalo Livre de Doença , Receptores ErbB/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Inibidores de Proteínas Quinases
17.
Nat Commun ; 14(1): 2859, 2023 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-37208329

RESUMO

The programmed cell death protein 1 (PD-1) is an inhibitory receptor on T cells and plays an important role in promoting cancer immune evasion. While ubiquitin E3 ligases regulating PD-1 stability have been reported, deubiquitinases governing PD-1 homeostasis to modulate tumor immunotherapy remain unknown. Here, we identify the ubiquitin-specific protease 5 (USP5) as a bona fide deubiquitinase for PD-1. Mechanistically, USP5 interacts with PD-1, leading to deubiquitination and stabilization of PD-1. Moreover, extracellular signal-regulated kinase (ERK) phosphorylates PD-1 at Thr234 and promotes PD-1 interaction with USP5. Conditional knockout of Usp5 in T cells increases the production of effector cytokines and retards tumor growth in mice. USP5 inhibition in combination with Trametinib or anti-CTLA-4 has an additive effect on suppressing tumor growth in mice. Together, this study describes a molecular mechanism of ERK/USP5-mediated regulation of PD-1 and identifies potential combinatorial therapeutic strategies for enhancing anti-tumor efficacy.


Assuntos
MAP Quinases Reguladas por Sinal Extracelular , Receptor de Morte Celular Programada 1 , Animais , Camundongos , Proteases Específicas de Ubiquitina/genética , Proteases Específicas de Ubiquitina/metabolismo , Homeostase , Imunoterapia
18.
Carbohydr Polym ; 314: 120907, 2023 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-37173014

RESUMO

Breast cancer is one of the most threatening cancers that poses a great risk to women's health. The anti-tumor drug doxorubicin (DOX) is one of commonly used drugs in the treatment of breast cancer. However, the cytotoxicity of DOX has always been an urgent challenge to be solved. In this study, we report an alternative drug delivery system delivering DOX for reducing its physiological toxicity by using the yeast ß-glucan particle (YGP) with a hollow and porous vesicle structure. Briefly, amino groups were grafted onto the surface of YGP with the silane coupling agent, then the oxidized hyaluronic acid (OHA) was attached by Schiff base reaction to get HA-modified YGP (YGP@N=C-HA), finally DOX was encapsulated into YGP@N=C-HA to get DOX-loaded YGP@N=C-HA (YGP@N=C-HA/DOX). In vitro release experiments exhibited the pH-responsive DOX release from YGP@N=C-HA/DOX. Cell experiments displayed that YGP@N=C-HA/DOX had good killing effect on both MCF-7 and 4T1 cells and could be internalized into these cells through CD44 receptors, showing targetability to cancer cells. Furthermore, YGP@N=C-HA/DOX could effectively inhibit tumor growth and reduce the physiological toxicity of DOX. Thus, the YGP-based vesicle provides an alternative strategy for lowering the physiological toxicity of DOX in the medical treatment of breast cancer.


Assuntos
Neoplasias da Mama , Nanopartículas , beta-Glucanas , Feminino , Humanos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Ácido Hialurônico/química , Saccharomyces cerevisiae , beta-Glucanas/farmacologia , beta-Glucanas/uso terapêutico , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Doxorrubicina/química , Sistemas de Liberação de Medicamentos , Nanopartículas/química , Células MCF-7
19.
Oncologist ; 28(6): e397-e405, 2023 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-37116899

RESUMO

BACKGROUND: The purpose of this analysis was to investigate the effectiveness of afatinib compared to that of osimertinib in patients with non-small cell lung cancer (NSCLC) who harbored uncommon epidermal growth factor receptor (EGFR) mutations. METHODS: A PubMed database-based literature review was conducted to retrieve related studies. Patients harboring EGFR mutations besides the deletion in exon 19 (19del) and point mutation of L858R were included in this analysis. The primary outcome events were the objective response rate (ORR) and progression-free survival (PFS). Propensity score matching (PSM) at a ratio of 1:1 was used between afatinib and osimertinib groups to control the confounding factors. Uncommon EGFR mutations were categorized into 4 groups: insertion in exon 20 (ex20ins), non-ex20ins single uncommon EGFR mutations, compound EGFR mutations that with 19del or L858R, and compound EGFR mutations without 19del or L858R. RESULTS: After PSM, 71 patients in either the afatinib or osimertinib group were matched. The afatinib group had an ORR of 60.6%, slightly higher than the osimertinib group's (50.3%), the difference was not statistically significant (P = .610). However, the afatinib group showed a significantly superior PFS benefit than the osimertinib group (11.0 vs. 7.0 months, P = .044). In addition, patients harboring non-ex20ins single uncommon EGFR mutations yield the best ORR and PFS, following treatment of either afatinib (ORR: 76.7%, mPFS: 14.1 months) or osimertinib (ORR: 68.8%, mPFS: 15.1 months). Moreover, there was no significant difference in terms of ORR or PFS between the cohort of patients treated with afatinib or osimertinib, regardless of whether or not the patients had brain metastases. CONCLUSIONS: Both afatinib and osimertinib displayed favorable clinical activities toward uncommon EGFR mutations. Afatinib showed a more profound and durable PFS benefit than osimertinib, although no efficacy advantage was observed.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Afatinib/farmacologia , Afatinib/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Receptores ErbB/genética , Receptores ErbB/uso terapêutico , Mutação , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico
20.
Radiat Oncol ; 18(1): 66, 2023 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-37031167

RESUMO

OBJECTIVE: To evaluate the impact of bone marrow (BM) irradiation dose on acute haematologic toxicity (HT) in concurrent chemoradiotherapy for cervical cancer. METHODS: Sixty-nine patients with cervical cancer treated with curative or postoperative adjuvant therapy received weekly cisplatin concurrent chemotherapy (CCT) and intensity-modulated radiation therapy (IMRT). The whole pelvic bone marrow (PBM) was delineated and divided into three subsites: ilium (IL), lower pelvis (LP), and lumbosacral spine (LS). Associations between clinical variables, dose volume of BM, including PBM, IL, LP, and LS in the form of x-Vy (volume receiving y Gy for x), and blood cell count nadir were tested using linear regression models. Receiver operating characteristic (ROC) curve analysis was further used to analyse the cutoff values of the variables with p < 0.05 in the multivariate analysis. RESULTS: In 69 patients, the haemoglobin nadir was positive correlated with baseline haemoglobin (p < 0.001), negative correlated with relative LP-V10 (p = 0.005), relative LP-V25 (p = 0.002), relative LP-V50 (p = 0.007), relative LP-mean (p = 0.003), absolute LP-V15 (p = 0.049), absolute LP-V25 (p = 0.004) and absolute LP-V30 (p = 0.009). The platelet nadir was positive correlated with baseline platelets (p = 0.048) and negative correlated with relative LP-V40 (p = 0.028), but there was no significant variable in absolute radiation volume by multivariate analysis. No variables related to the neutrophil nadir were found, and the 69 patients were divided into group A (43 cases) receiving 3-4 cycles of CCT and group B (26 cases) receiving 5-6 cycles of CCT. In group A, the relative IL-V15 (p = 0.014), the relative IL-V50 (p = 0.010) and the absolute LP-V50 (p = 0.011) were negative correlated with the neutrophil nadir. No significant variable was found in group B. No significant variables related to the lymphocyte nadir were found, and the neutrophil-to-lymphocyte ratio (NLR) was analysed. Age (p < 0.05), relative LP-V15 (p = 0.037) and absolute PBM-mean (p < 0.001) were found to be negative related to NLR. CONCLUSION: The dosimetric parameters of relative irradiated volume of BM have more statistically significant datas on acute HT than absolute irradiated volume. The nadir of haemoglobin and platelets and the vertice of NLR were more affected by the irradiation dose to LP, while neutrophils were more affected by the dose to IL. Acute HT was negative related to both low-dose irradiation (V10-30) and high-dose irradiation (V40, V50). For more than 4 cycles of CCT, the effect of BM irradiation on the neutrophils nadir was masked by chemotherapy.


Assuntos
Radioterapia de Intensidade Modulada , Neoplasias do Colo do Útero , Feminino , Humanos , Medula Óssea/efeitos da radiação , Dosagem Radioterapêutica , Neoplasias do Colo do Útero/radioterapia , Quimiorradioterapia/efeitos adversos , Radioterapia de Intensidade Modulada/efeitos adversos , Hemoglobinas
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