RESUMEN
Colorectal cancer (CRC) is the third most common cancer worldwide and the second most common cause of cancer death. Nanotherapies are able to selectively target the delivery of cancer therapeutics, thus improving overall antitumor efficiency and reducing conventional chemotherapy side effects. Mesoporous silica nanoparticles (MSNs) have attracted the attention of many researchers due to their remarkable advantages and biosafety. We offer insights into the recent advances of MSNs in CRC treatment and their potential clinical application value.
RESUMEN
BACKGROUND: Ferroptosis is a distinct form of cell death characterized by unique morphology, biochemistry, and genetics, playing a crucial role in the initiation, progression, prognosis, and therapeutic strategies of tumors. However, the impact of ferroptosis-related genes (FRGs) on the tumor microenvironment (TME) remains unclear. This study may advance the existing knowledge of FRGs in gastric cancer, and push ahead with more effective prognostic assessment and the development of more effective immunotherapy approaches. METHODS: FRGs were acquired from the FerrDb database and a consensus clustering technique was adopted to categorize patients with GC into groups in line with the expression profiles of 44 FRGs in order to further investigate the expression properties of these proteins. Assessment of the immune status, microsatellite instability (MSI) and cancer stem cell (CSC) index between the high- and low- risk groups to assess the proportion of TIICs in the TME, ssGSVA was adopted to detect the abundance of infiltrating immune cells from the low-risk and high-risk groups. Expression levels of eight ferroptosis-related genes of prognostic signature in GC tissues and adjacent normal tissues was detected by RT-PCR. RESULTS: In the GC cohort, TP53 has the highest mutation frequency (44 %), and was shown to be highly linked with the expression levels of 11 FRGs. In accordance with the Kaplan-Meier curve, the overall survival time of patients with subtype A (Low FRG-score) discernibly exceeded that of patients with subtype B (High FRG-score).In addition, there is a significant difference in the infiltration of most immune cells between subtype A and subtype B, and some important immune checkpoints (CTLA4, PDCD1, CD274, LAG3, PDCD1LG2, and HAVCR2) have higher expression in cluster A. Finally, low FRG-scores were significantly associated with MSI-H status, while high FRG-scores were significantly associated with microsatellite stable status (MSS). FRG-score is negatively related to the cancer stem cell (CSC). CONCLUSION: Low FRG-score, due to its high microsatellite instability (MSI-H), high mutational load and immune activation, indicates the possible advantage of OS. In addition, the FRG-score was closely related to the cancer stem cell (CSC) index and the sensitive degree of chemotherapeutic drug.
Asunto(s)
Ferroptosis , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/genética , Pronóstico , Ferroptosis/genética , Inestabilidad de Microsatélites , Microambiente Tumoral/genéticaRESUMEN
Rationale: Mitochondria generate ATP via the oxidative phosphorylation system, which mainly comprises five respiratory complexes found in the inner mitochondrial membrane. A high-order assembly of respiratory complexes is called a supercomplex. COX7A2L is a supercomplex assembly factor that has been well-investigated for studying supercomplex function and assembly. To date, the effects of mitochondrial supercomplexes on cell metabolism have not been elucidated. Methods: We depleted COX7A2L or Cox7a2l in human and mouse cells to generate cell models lacking mitochondrial supercomplexes as well as in DBA/2J mice as animal models. We tested the effect of impaired supercomplex assembly on cell proliferation with different nutrient supply. We profiled the metabolic features in COX7A2L-/- cells and Cox7a2l-/- mice via the combined use of targeted and untargeted metabolic profiling and metabolic flux analysis. We further tested the role of mitochondrial supercomplexes in pancreatic ductal adenocarcinoma (PDAC) through PDAC cell lines and a nude mouse model. Results: Impairing mitochondrial supercomplex assembly by depleting COX7A2L in human cells reprogrammed metabolic pathways toward anabolism and increased glutamine metabolism, cell proliferation and antioxidative defense. Similarly, knockout of Cox7a2l in DBA/2J mice promoted the use of proteins/amino acids as oxidative carbon sources. Mechanistically, impaired supercomplex assembly increased electron flux from CII to CIII/CIV and promoted CII-dependent respiration in COX7A2L-/- cells which further upregulated glutaminolysis and glutamine oxidation to accelerate the reactions of the tricarboxylic acid cycle. Moreover, the proliferation of PDAC cells lacking COX7A2L was inhibited by glutamine deprivation. Conclusion: Our results reveal the regulatory role of mitochondrial supercomplexes in glutaminolysis which may fine-tune the fate of cells with different nutrient availability.
Asunto(s)
Complejo IV de Transporte de Electrones , Glutamina , Ratones , Humanos , Animales , Glutamina/metabolismo , Complejo IV de Transporte de Electrones/metabolismo , Ratones Endogámicos DBA , Mitocondrias/metabolismo , Membranas Mitocondriales/metabolismo , Mamíferos/metabolismoRESUMEN
Objective: In this research, we investigated the current status, hotspots, frontiers, and trends of research in the field of bone-tendon interface (BTI) from 2000 to 2023, based on bibliometrics and visualization and analysis in CiteSpace, VOSviewer, and a bibliometric package in R software. Methods: We collected and organized the papers in the Web of Science core collection (WoSCC) for the past 23 years (2000-2023), and extracted and analyzed the papers related to BTI. The extracted papers were bibliometrically analyzed using CiteSpace for overall publication trends, authors, countries/regions, journals, keywords, research hotspots, and frontiers. Results: A total of 1,995 papers met the inclusion criteria. The number of papers published and the number of citations in the field of BTI have continued to grow steadily over the past 23 years. In terms of research contribution, the United States leads in terms of the number and quality of publications, number of citations, and collaborations with other countries, while the United Kingdom and the Netherlands lead in terms of the average number of citations. The University of Leeds publishes the largest number of papers, and among the institutions hosting the 100 most cited papers Hospital for Special Surgery takes the top spot. MCGONAGLE D has published the highest number of papers (73) in the last 10 years. The top three clusters include #0 "psoriatic arthritis", #1 "rotator cuff repair", and #2 "tissue engineering". The structure and function of the BTI and its key mechanisms in the healing process are the key to research, while new therapies such as mechanical stimulation, platelet-rich plasma, mesenchymal stem cells, and biological scaffolds are hot topics and trends in research. Conclusion: Over the past 23 years, global research on the BTI has expanded in both breadth and depth. The focus of research has shifted from studies concentrating on the structure of the BTI and the disease itself to new therapies such as biomaterial-based alternative treatments, mechanical stimulation, platelet-rich plasma, etc.
RESUMEN
Gefitinib has shown good efficacy in patients with EGFR mutation-positive non-small-cell lung cancer, but acquired resistance is inevitable. Here we report a patient with an advanced lung adenocarcinoma with the EGFR mutation who achieved surgical opportunity and long-term survival following treatment with chemotherapy and bevacizumab, followed by sequential gefitinib combined with allogeneic haploidentical CD8+ CD56+ natural killer T cells. Our case provides a potential effective strategy for delaying acquired gefitinib resistance and extending progression-free survival among patients with non-small-cell lung cancer who harbor common EGFR mutations.
As one of the EGFR tyrosine kinase inhibitors used clinically, gefitinib has achieved good efficacy in patients with EGFR mutation-positive non-small-cell lung cancer (NSCLC), though eventual drug resistance is inevitable. Currently, the efficacy of anti-PD-1/anti-PD-L1 immunotherapy has not been demonstrated in NSCLC because of the low expression of PD-1 in this disease. Thus new strategies for NSCLC treatment need to be further explored. Here we report a patient with advanced lung adenocarcinoma with the EGFR mutation, who was treated with chemotherapy and bevacizumab and sequential gefitinib combined with allogeneic haploidentical natural killer T cells, who achieved a surgical opportunity and long-term survival. To delay the time to resistance to gefitinib, a combination of allogeneic haploidentical CD8+ CD56+ natural killer T cells and gefitinib may offer a viable treatment option for patients with EGFR mutation-positive NSCLC.
Asunto(s)
Adenocarcinoma del Pulmón , Adenocarcinoma , Antineoplásicos , Carcinoma de Pulmón de Células no Pequeñas , Trasplante de Células Madre Hematopoyéticas , Neoplasias Pulmonares , Células T Asesinas Naturales , Humanos , Gefitinib/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Quinazolinas/uso terapéutico , Receptores ErbB/genética , Neoplasias Pulmonares/tratamiento farmacológico , Adenocarcinoma/tratamiento farmacológico , Antineoplásicos/uso terapéutico , Adenocarcinoma del Pulmón/tratamiento farmacológico , Mutación/genética , Inhibidores de Proteínas Quinasas/uso terapéuticoRESUMEN
BACKGROUND: Rectal foreign bodies (RFB) are quite uncommon except in very busy hospitals. Because of their rarity, it is seldom that the treating physicians have a standard approach to the diagnosis, technique of extraction, and post-extraction evaluation. This can be further complicated by the rather extreme variability of size, shape, and texture of the foreign bodies, as well as the potential extent of trauma to the rectum or distal colon. AIM: The objectives of this study were to delineate the demographics, classification of cause, and injury patterns of RFB and to present the results of the transanal surgical management of a large series of RFB. METHODS: We retrospectively collected extensive data from the hospital medical records of the 291 patients who presented with RFB to the emergency department of Shenyang Proctological Hospital (Shenyang, China) from 2012 July to 2020 December. Specifically, demographics, origins and circumstance of the RFB, complications, injuries, anesthesia method, and the results of the transanal surgical management were recorded and analyzed. RESULTS: Of the 291 RFB cases, 225 (77.3%) were male and 66 (22.7%) were female, with a mean age of 53.8 ± 15.5 years (range, 1 ~ 88 years). The circumstances of the RFB were categorized as swallowed, 199 cases (68.4%); self-inserted, 87 (29.9%); and iatrogenic, 5 (1.7%). The proportion of males in the self-inserted RFB group was significantly greater than the swallowed RFB group (t = 31.114, p = 0.000). In the swallowed RFB group, the most common anorectal injuries and pathological changes were the following: penetration into the mucosa (75 cases, 37.7%), perianal or submucosal abscess (27 cases, 13.6%), and penetration into the anal canal (18 cases, 9.0%). In the self-inserted RFB group, 64 (73.6%) of the 87 cases had an intact rectum, whereas 8 (9.2%) had rectal mucosal ulcers and bleeding, and 7 (8%) had rectal lacerations. In the iatrogenic RFB group, 3 cases (60%) had rectal mucosal ulcers and bleeding, and 2 cases (40%) had inflammation of the rectal mucosa. Regarding extraction procedures, in the swallowed group, 187(187/199; 94%) patients underwent a transanal surgical procedure, and all were successful. In the self-inserted group, 82 patients underwent the transanal surgical procedure, and 74 (74/82; 90.2%) were successful whereas it was unsuccessful in the remaining 8 patients (8/82, 9.8%). Three (3/4, 75%) patients with iatrogenic RFB were resolved by the transanal surgical procedure. CONCLUSION: Men were markedly more likely than women to have swallowed RFBs and self-inserted RFBs. No serious damage to the rectum and anus was found in cases of swallowed RFB. Moreover, most surgical operations to remove foreign bodies via the anus were successful in this category of RFB. In contrast, rectal injury was more severe in patients with self-inserted RFB, such as rectal laceration, rectal mucosal ulcer, and bleeding. Moreover, the transanal removal operation in patients with self-inserted RFB had a failure rate of nearly 10%. Thick, long, hard foreign bodies did present a great challenge to the operator. Therefore, if necessary, patients with foreign bodies may need to be promptly referred for transabdominal removal.
Asunto(s)
Cuerpos Extraños , Úlcera , Adulto , Anciano , Femenino , Cuerpos Extraños/complicaciones , Cuerpos Extraños/cirugía , Humanos , Enfermedad Iatrogénica , Masculino , Persona de Mediana Edad , Recto/cirugía , Estudios Retrospectivos , Úlcera/complicacionesRESUMEN
Angiopoietin-2 (Ang2), a member of the angiopoietin family, is widely involved in the process of vascular physiology, bone physiology, adipose tissue physiology and the occurrence and development of inflammation, cardiac hypertrophy, rheumatoid, tumor and other diseases under pathological conditions. Proliferation and metastasis of cancer largely depend on angiogenesis. Therefore, anti-angiogenesis has become the target of tumor therapy. Due to the Ang2 plays a key role in promoting angiogenesis and stability in vascular physiology, the imbalance of its expression is an important condition for the occurrence and development of cancer. It has been proved that blocking Ang2 can inhibit the growth, invasion and metastasis of cancer cells. In recent years, research has been constantly supplemented. We focus on the mechanisms that regulate the expression of Ang2 mRNA and protein levels in different cancers, contributing to a better understanding of how Ang2 exerts different effects in different cancers and stages, as well as facilitating more specific targeting of relevant molecules in cancer therapy. At the same time, the importance of Ang2 in cancer growth, metastasis, prognosis and combination therapy is pointed out. And finally, we will discuss the current investigations and future challenges of combining Ang2 inhibition with chemotherapy, immunotherapy, and radiotherapy to increase its efficacy in cancer patients. This review provides a theoretical reference for the development of new targets and effective combination therapy strategies for cancer treatment in the future.
Asunto(s)
Angiopoyetina 2 , Neoplasias , Angiopoyetina 2/genética , Angiopoyetina 2/metabolismo , Humanos , Neoplasias/tratamiento farmacológico , Neovascularización Patológica/metabolismo , ARN Mensajero/genéticaRESUMEN
Acetyl-CoA synthetase 2 (ACSS2), an important member of the acetyl-CoA synthetase (ACSS) family, can catalyze the conversion of acetate to acetyl coenzyme A (acetyl-CoA). Currently, acetyl-CoA is considered an important intermediate metabolite in the metabolism of energy substrates. In addition, nutrients converge through acetyl-CoA into a common metabolic pathway, the tricarboxylic acid cycle and oxidative phosphorylation. Not only does ACSS2 play a crucial role in material energy metabolism, it is also involved in the regulation of various acetylation processes, such as regulation of histone and transcription factor acetylation. ACSS2-mediated regulation of acetylation is related to substance metabolism and tumorigenesis. In mammalian cells, ACSS2 utilizes intracellular acetate to synthesize acetyl-CoA, a step in the process of DNA and histone acetylation. In addition, studies in tumors have shown that cancer cells adapt to the growth conditions in the tumor microenvironment (TME) by activating or increasing the expression level of ACSS2 under metabolic stress. Therefore, this review mainly outlines the role of ACSS2 in substance metabolism and tumors and provides insights useful for investigating ACSS2 as a therapeutic target.
RESUMEN
Acetyl-CoA Synthetase 2 (ACSS2) belongs to a member of the acyl-CoA short-chain synthase family, which can convert acetate in the cytoplasm and nucleus into acetyl-CoA. It has been proven that ACSS2 is highly expressed in glioblastoma, breast cancer, liver cancer, prostate cancer, bladder cancer, renal cancer, and other tumors, and is closely related to tumor stage and the overall survival rate of patients. Accumulating studies show that hypoxia and a low serum level induce ACSS2 expression to help tumor cells cope with this nutrient-poor environment. The potential mechanisms are associated with the ability of ACSS2 to promote the synthesis of lipids in the cytoplasm, induce the acetylation of histones in the nucleus, and facilitate the expression of autophagy genes. Novel-specific inhibitors of ACSS2 are developed and confirmed to the effectiveness in pre-clinical tumor models. Targeting ACSS2 may provide novel approaches for tumor treatment. This review summarizes the biological function of ACSS2, its relation to survival and prognosis in different tumors, and how ACSS2 mediates different pathways to promote tumor metastasis, invasion, and drug resistance.
RESUMEN
Bromodomain-containing protein 4 (BRD4), a member of the bromodomain and extraterminal (BET) family, is considered to be a major driver of cancer cell growth and a new target for cancer therapy. Over 30 targeted inhibitors currently in preclinical and clinical trials have significant inhibitory effects on various tumors, including acute myelogenous leukemia (AML), diffuse large B cell lymphoma, prostate cancer, breast cancer and so on. However, resistance frequently occurs, revealing the limitations of BET inhibitor (BETi) therapy and the complexity of the BRD4 expression mechanism and action pathway. Current studies believe that when the internal and external environmental conditions of cells change, tumor cells can directly modify proteins by posttranslational modifications (PTMs) without changing the original DNA sequence to change their functions, and epigenetic modifications can also be activated to form new heritable phenotypes in response to various environmental stresses. In fact, research is constantly being supplemented with regards to that the regulatory role of BRD4 in tumors is closely related to PTMs. At present, the PTMs of BRD4 mainly include ubiquitination and phosphorylation; the former mainly regulates the stability of the BRD4 protein and mediates BETi resistance, while the latter is related to the biological functions of BRD4, such as transcriptional regulation, cofactor recruitment, chromatin binding and so on. At the same time, other PTMs, such as hydroxylation, acetylation and methylation, also play various roles in BRD4 regulation. The diversity, complexity and reversibility of posttranslational modifications affect the structure, stability and biological function of the BRD4 protein and participate in the occurrence and development of tumors by regulating the expression of tumor-related genes and even become the core and undeniable mechanism. Therefore, targeting BRD4-related modification sites or enzymes may be an effective strategy for cancer prevention and treatment. This review summarizes the role of different BRD4 modification types, elucidates the pathogenesis in the corresponding cancers, provides a theoretical reference for identifying new targets and effective combination therapy strategies, and discusses the opportunities, barriers, and limitations of PTM-based therapies for future cancer treatment.
RESUMEN
OBJECTIVES: Vaccinations can prevent COVID-19 and control its spread quickly and efficiently. This study aimed to investigate knowledge and willingness of geriatric care facility staff to receive a COVID-19 vaccine, and to provide a basis for the government to promote the COVID-19 vaccine and guide people to get vaccinated. STUDY DESIGN: A cross-sectional study. METHODS: Data on characteristics of the participants, knowledge about the COVID-19 vaccine, and willingness to get vaccinated for COVID-19 were collected through an online survey from May 19 to June 18, 2021. Statistical analyses were conducted with ANOVA, chi-square, logistic regression. RESULTS: The survey illustrated that the highest score of COVID-19 vaccine knowledge was 50, the lowest 20, and the average 44.22. It also demonstrated that 91.3% of the participants had a good knowledge of COVID-19 vaccine, and that 97.3% participants were willing to receive the COVID-19 vaccine. The results showed that geriatric care facility staff had varied level of the COVID-19 vaccine knowledge depending upon their age, educational background, and other factors, and correspondingly, their willingness to receive COVID-19 vaccine was affected by their knowledge level of COVID-19 vaccine. CONCLUSIONS: In general, the participants, the staff of geriatric care facilities in Anhui Province, had good mastery of the COVID-19 vaccine, and they were willing to get vaccinated. However, there still existed a few participants with poor knowledge, who were unwilling to get vaccinated against COVID-19. Government can guide people to accept vaccination by enhancing publicity about the effects and adverse reactions of COVID-19 vaccines.
Asunto(s)
Vacunas contra la COVID-19 , COVID-19 , Anciano , COVID-19/prevención & control , China , Estudios Transversales , Humanos , SARS-CoV-2 , VacunaciónRESUMEN
Solute carrier family 7 member 11 (SLC7A11) is a major transporter regulating cysteine metabolism and is widely expressed in a variety of tumor cells. SLC7A11 plays an important role in the occurrence, development, invasion and metastasis of tumors by regulating the transport of cysteine in the tumor microenvironment. SLC7A11 is expected to become a new therapeutic target and prognostic indicator for the individualized treatment of patients. According to relevant research reports, SLC7A11 can predict the stages and metastasis of liver, breast and lung cancer. Therefore, an in-depth exploration of the role of SLC7A11 in tumors may be important for the screening, early diagnosis, treatment and prognosis of patients with tumors. The current review summarizes the research progress on SLC7A11 in liver cancer, lung cancer and other tumors on the basis of previous primary studies. In addition, the present review systematically elaborates on the three main aspects of SLC7A11 pathways in some tumors, the cancer-promoting mechanisms, and the therapeutic relationship between SLC7A11 and tumors. Finally, the present review aims to provide a reference for assessing whether SLC7A11 can be used as a prognostic indicator and treatment target for tumor patients, and the future research direction with regard to SLC7A11 in tumors.
RESUMEN
The low sensitivity of radiotherapy is the main cause of tumor tolerance against ionizing radiation (IR). However, the molecular mechanisms by which radiosensitivity is controlled remain elusive. Here, we observed that high expression of pellino E3 ubiquitin protein ligase 1 (PELI1) was correlated with improved prognosis in human esophageal squamous cell carcinoma stage III patients that received adjuvant radiotherapy. Moreover, we found PELI1-mediated IR-induced tumor cell apoptosis in vivo and in vitro. Mechanistically, PELI1 mediated the lysine 48 (Lys48)-linked polyubiquitination and degradation of NF-κB-inducing kinase (NIK; also known as MAP3K14), the master kinase of the noncanonical NF-κB pathway, thereby inhibiting IR-induced activation of the noncanonical NF-κB signaling pathway during radiotherapy. As a consequence, PELI1 inhibited the noncanonical NF-κB-induced expression of the anti-apoptotic gene BCL2 like 1 (Bclxl; also known as BCL2L1), leading to an enhancement of the IR-induced apoptosis signaling pathway and ultimately promoting IR-induced apoptosis in tumor cells. Therefore, Bclxl or NIK knockdown abolished the apoptosis-resistant effect in PELI1-knockdown tumor cells after radiotherapy. These findings establish PELI1 as a critical tumor intrinsic regulator in controlling the sensitivity of tumor cells to radiotherapy through modulating IR-induced noncanonical NF-κB expression.
Asunto(s)
Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Proteínas Nucleares , Ubiquitina-Proteína Ligasas , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/radioterapia , Carcinoma de Células Escamosas de Esófago/genética , Carcinoma de Células Escamosas de Esófago/radioterapia , Humanos , Ligasas , FN-kappa B/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Tolerancia a Radiación , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
OBJECTIVE: To establish a testicular Occludin gene knockout model in mice and observe the phenotypic changes. METHODS: Occludin-floxed (genotype Floxp/-) mice were constructed based on the Cre/loxp system, which were cross-bred with AQP2-cre (genotype Cre/-) mice to derive Occludin knockout mice (Genotype Floxp/Floxp Cre/-). The genotype of the F1 knockout mice was identified by PCR and Southern blot technology. The expression of the Occludin protein in the knockout mice was determined by qPCR, Western blot and immunohistochemistry to verify the success of the modeling. Comparisons were made in the sperm count between the model and normal mice, followed by analysis of their fertility. RESULTS: The target mice of Occludin knockout were successfully constructed, which, compared with the normal controls, showed significantly down-regulated expression of the occludin protein, decreased sperm count and reduced fertility (P < 0.05). CONCLUSIONS: Occludin gene knockout mice were successfully constructed, and deletion of Occludin affects the reproductive function of the mice.
Asunto(s)
Infertilidad Masculina/genética , Ocludina , Testículo , Animales , Modelos Animales de Enfermedad , Técnicas de Inactivación de Genes , Masculino , Ratones , Ratones Noqueados , Ocludina/genéticaRESUMEN
OBJECTIVE: To study the transcription factors of the spermatogenesis-related promoter mir-122-5p. METHODS: SP1 and GATA4 were predicted as the possible transcription factors of the mir-122-5p promoter by bioinformatics analysis, followed by construction of the double luciferase pGL3-mir-122-5p promoter vector, pcDNA3.1 (+) -SP1 expression vector and pcDNA3.1 (+) -GATA4 expression vector, respectively. The pcDNA-SP1+pGL3-basic mixture plasmid and pcDNA-SP1+ pGL3-miR-122-5p promoter mixture plasmid, pcDNA-GATA4+pGL3-basic mixture plasmid and pcDNA-GATA4+pGL3-miR-122-5p promoter mixture plasmid were transferred into 293T cells. The enzyme activity was detected the Dual-Luciferase Reporter Assay System. RESULTS: The fluorescence value of the pcDNA3.1+pGL3-miR-122 promoter was 0.0362 ± 0.0004, significantly higher than that of the pcDNA3.1+pGL3-basic group (P < 0.05), indicating the successful construction of the mouse miR-122-5p promoter luciferase reporter plasmid. The fluorescence value was markedly higher in the pcDNA -SP1 + pGL3-miR-122-5p promoter than in the pcDNA -SP1+pGL3-basic group, suggesting that the transcription factor SP1 could promote the transcription of miR-122. There was no statistically significant difference in the fluorescence value between the pcDNA -gata4+pGL3-basic transfection and pcDNA -GATA4+pGL3-miR-122-5p promoter transfection groups, indicative of the inability of GATA4 to promote the transcription of miR-122-5p. CONCLUSIONS: The transcription factor SP1, rather than GATA4, can promote the transcription of miR-122-5p.
Asunto(s)
MicroARNs , Factores de Transcripción , Animales , Ratones , MicroARNs/genética , Factores de Transcripción/genéticaRESUMEN
OBJECTIVE: To investigate the role of occludin in tight junction (TJ) in vitro. METHODS: We constructed RNA interfering lentiviral vectors and transfected them into TM4 cells. Then we detected their inhibitory effect on occuldin by RT-PCR and Western blot and analyzed the role of occuldin in TJ using an in vitro TJ cell model. RESULTS: The pLenti 6.3-EGFP-occludin-miR expression vector was successfully constructed. The results of RT-PCR and Western blot showed that pLenti 6.3-EGFP-occludin-miR-3 significantly inhibited the expression of occludin (P < 0.05), which was remarkably lower than in the blank control and the pLenti 6.3- EGFP transfection group (0.7534 ± 0.089 vs 1.000 and 1.056 ± 0.025, P < 0.05). The expression of occludin was markedly suppressed and the tightness of tight junctions decreased in the TM4 cells transfected with pLenti 6.3-EGFP-occludin-miR-3. CONCLUSIONS: The pLenti 6.3-EGFP-occludin-miR expression vector was successfully constructed, and occludin is one of the functional proteins that maintain tight junctions.
Asunto(s)
Ocludina , Interferencia de ARN , Uniones Estrechas , Animales , Línea Celular , Lentivirus , Ratones , Ocludina/genéticaRESUMEN
Obesity, a global epidemic, is an independent risk factor for the occurrence and development of a variety of tumors, such as breast cancer, pancreatic cancer, ovarian cancer and colorectal cancer. Adipocytes are important endocrine cells in the tumor microenvironment of obesity-related tumors, which can secrete a variety of adipokines (such as leptin, adiponectin, estrogen, resistin, MIF and MCP-1, etc.), among which leptin, adiponectin and estrogen are the most in-depth and valuable ones. These adipokines are closely related to tumorigenesis and the progression of tumors. In recent years, more and more studies have shown that under chronic inflammatory conditions such as obesity, adipocytes secrete more adipokines to promote the tumorigenesis and development of tumors. However, it is worth noting that although adiponectin is also secreted by adipocytes, it has an anti-tumor effect, and can cross-talk with other adipokines (such as leptin and estrogen) and insulin to play an anti-tumor effect together. In addition, obesity is the main cause of insulin resistance, which can lead to the increase of the expression levels of insulin and insulin-like growth factor (IGF). As important regulators of blood glucose and lipid metabolism, insulin and IGF also play an important role in the progress of obesity related tumors. In view of the important role of adipokines secreted by adipocytes and insulin/IGF in tumors, this article not only elaborates leptin, adiponectin and estrogen secreted by adipocytes and their mechanism of action in the development of obesity- related tumors, but also introduces the relationship between insulin/IGF, a regulator of lipid metabolism, and obesity related tumors. At the same time, it briefly describes the cancer-promoting mechanism of resistin, MIF and MCP-1 in obesity-related tumors, and finally summarizes the specific treatment opinions and measures for various adipokines and insulin/insulin-like growth factors in recent years.
RESUMEN
BACKGROUND: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib, have achieved good efficacy in EGFR mutation-positive non-small-cell lung cancer (NSCLC) patients, but eventual drug resistance is inevitable. Thus, new TKI-based combination therapies should be urgently explored to extend the overall survival time of these patients. CD8 + CD56+ natural killer T (NKT) cells are a natural and unique subset of lymphocytes in humans that present characteristics of T and NK cells and exert cytotoxicity on tumour cells in a granzyme B-dependent manner. The aim of this trial was to explore the efficacy and safety of CD8 + CD56+ NKT cell immunotherapy combined with gefitinib in patients with advanced EGFR-mutated NSCLC. METHODS: The study was designed as a prospective, randomized, controlled, open-label, phase I/II trial that includes 30 patients with EGFR mutation-positive stage III/IV NSCLC. All patients will be randomized in blocks at a 1:1 ratio and treated with gefitinib 250 mg/day monotherapy or combination therapy with allogeneic CD8 + CD56+ NKT cell infusions twice per month for 12 cycles or until disease progression occurs. The effectiveness of this treatment will be evaluated based on by progression-free survival (PFS), the time to progression (TTP), overall response rate (ORR), disease control rate (DCR) and overall survival (OS). The safety of the trail is being assessed based on adverse events (AEs). Recruitment and data collection, which started in December 2017, are ongoing. DISCUSSION: Although immunotherapy, including programmed death-1/programmed death-1 ligand (PD-1/PD-L1) immunotherapy, has been used for NSCLC treatment with or without EGFR-TKIs, its clear efficacy still has not been shown. Assessing the safety and therapeutic potential of allogeneic CD8 + CD56+ NKT killer cells in combination with EGFR-TKIs in NSCLC will be of great interest. TRIAL REGISTRATION: This trial (Phase I/II Trails of NKT Cell in Combination With Gefitinib For Non Small Cell Lung Cancer) was registered on 21 November 2017 with www.chictr.org.cn , ChiCTR-IIR-17013471 .
Asunto(s)
Traslado Adoptivo , Carcinoma de Pulmón de Células no Pequeñas/terapia , Gefitinib/uso terapéutico , Neoplasias Pulmonares/terapia , Mutación , Células T Asesinas Naturales/inmunología , Traslado Adoptivo/efectos adversos , Traslado Adoptivo/métodos , Antígeno B7-H1/antagonistas & inhibidores , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Carcinoma de Pulmón de Células no Pequeñas/etiología , Terapia Combinada , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/genética , Gefitinib/administración & dosificación , Gefitinib/efectos adversos , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/etiología , Terapia Molecular Dirigida , Células T Asesinas Naturales/metabolismo , Resultado del TratamientoRESUMEN
BACKGROUND: The most common causes of outlet obstructive constipation (OOC) are rectocele and internal rectal prolapse. The surgical methods for OOC are diverse and difficult, and the postoperative complications and recurrence rate are high, which results in both physical and mental pain in patients. With the continuous deepening of the surgeon's concept of minimally invasive surgery and continuous in-depth research on the mechanism of OOC, the treatment concepts and surgical methods are continuously improved. AIM: To determine the efficacy of the TST36 stapler in the treatment of rectocele combined with internal rectal prolapse. METHODS: From January 2017 to July 2019, 49 female patients with rectocele and internal rectal prolapse who met the inclusion criteria were selected for treatment using the TST36 stapler. RESULTS: Forty-five patients were cured, 4 patients improved, and the cure rate was 92%. The postoperative obstructed defecation syndrome score, the defecation frequency score, time/straining intensity, and sensation of incomplete evacuation were significantly decreased compared with these parameters before treatment, and the differences were statistically significant (P < 0.05). The postoperative anal canal resting pressure and maximum squeeze pressure in patients decreased compared with before treatment, and the differences were statistically significant (P < 0.05). The initial and maximum defecation thresholds after surgery were significantly lower than those before treatment, and the differences were statistically significant (P < 0.05). The postoperative ratings of rectocele, resting phase, and defecation phase in these patients were significantly decreased compared with those before treatment, and the differences were statistically significant (P < 0.05). CONCLUSION: The TST36 stapler is safe and effective in treating rectocele combined with internal rectal prolapse and is worth promoting in clinical work.
RESUMEN
BACKGROUND: Occludin protein is the primary assembling protein of TJs and the structural basis for tight junction formation between Sertoli cells in the spermatogenic epithelium. The expression of miR-122-5p and occludin are negatively correlated. In order to investigate the regulation mechanism of miR-122-5p on occludin and TJ, the present study isolated primary Sertoli cells from C57BL/6 mice, identified a transcription factor of miR-122-5p in testicle, studied the modulating loci of miR-122-5p on occludin using a dual-luciferase reporter assay, analyzed the regulate of miR-122-5p on the expression of occludin with real-time RT-PCR and Western blot, and studied the effect of miR-122-5p on the tight junction using a Millicell Electrical Resistance System. RESULTS: The relative luciferase activity in the pcDNA-Sp1 + pGL3-miR-122-5p promoter group was significantly higher than that in the pcDNA-Sp1 + pGL3-basic group, which suggests that transcript factor Sp1 promotes the transcription of miR-122-5p. The relative luciferase activity in the occludin 3'-UTR (wt) + miR-122-5p mimic group was significantly lower than that in the other groups (p < 0.01), which indicates that miR-122-5p modulates the expression of occludin via the ACACTCCA sequence of the occludin-3'UTR. The levels of occludin mRNA and protein in the miR-122-5p mimic group were significantly lower than that in the other groups (p < 0.05), which indicates that miR-122-5p reduces the expression of occludin. The trans-epithelial resistance of the miR-122-5p mimic group was significantly lower than that of the blank control group after day 4 (p < 0.05), which indicates that miR-122-5p inhibited the assembly of the inter-Sertoli TJ permeability barrier in vitro. CONCLUSION: These results displayed that miR-122-5p could regulate tight junctions via the Sp1-miR-122-5p-occludin-TJ axis.
ABSTRAIT: CONTEXTE: La protéine occludine est. la principale protéine d'assemblage des jonctions serrées (JS), et la base structurelle pour la formation de ces jonctions entre les cellules de Sertoli dans l'épithélium séminifère. L'expression de miR-122-5p et de l'occludine sont négativement corrélées. Afin d'étudier le mécanisme de régulation de l'occludine et des TJ par miR-122-5p, nous avons, dans la présente étude, isolé des cellules primaires de Sertoli de souris C57BL/6, identifié un facteur de transcription de miR-122-5p dans le testicule, étudié les loci de miR-122-5p modulants l'occludine par le biais d'un système rapporteur à 2 luciférases, analysé la régulation de miR-122-5p sur l'expression de l'occludine par qRT-PCR et Western blot, et étudié l'effet de miR-122-5p sur les jonctions serrées à l'aide d'un Système de Résistance Electrique Millicell. RéSULTATS: L'activité relative de la luciférase dans le groupe du promoteur de pcDNA46 Sp1 + pGL3-miR-122-5p était significativement plus élevée que celle observée dans le groupe pcDNA-Sp1 + pGL3-basique, ce qui suggère que le facteur de transcription Sp1 favorise la transcription de miR-122-5p. L'activité relative de la luciférase dans le groupe 3'-UTR (wt) + miR-122-5p mimant l'occludine était significativement inférieure à celle des autres groupes (p < 0,01), ce qui indique que miR-122-5p module l'expression de l'occludine via la séquence ACACTCCA en 3' UTR de l'occludine. Les niveaux d'ARNm et de protéine occludine dans le groupe mimant miR-122-5p étaient significativement inférieurs à ceux des autres groupes (p < 0,05), ce qui indique que miR-122-5p inhibe l'expression de l'occludine. La résistance transépithéliale du groupe mimant miR-122-5p était significativement inférieure à celle du groupe témoin vierge après le jour 4 (p < 0.05), ce qui indique que miR-122-5p inhibe in vitro l'assemblage des jonctions serrées de la barrière de perméabilité inter-Sertolienne. CONCLUSIONS: Ces résultats montrent que miR-122-5p pourrait réguler les jonctions serrées via l'axe Sp1-miR-122-5p-occludine.