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1.
Biochim Biophys Acta Rev Cancer ; 1876(1): 188549, 2021 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-33894300

RESUMO

Molecular targeted therapy of cancer has always been the focus of clinicians. Among those therapeutic targets, the human epidermal growth factor receptor-2 (HER-2) signaling pathway is one of the most popular targets for translational research in cancer. However, unlike prospect in breast cancer, HER-2 inhibitor trastuzumab is the only molecular targeted drug approved by US Food and Drug Administration (FDA) for the first-line treatment of HER-2 positive advanced gastric cancer. On this basis, a variety of novel HER2- targeted drugs for gastric cancer are under development, and related clinical researches are in full swing, including small molecular kinase inhibitors (e.g., afatinib, neratinib, pyrotinib), antibody-drug conjugates (e.g., DS-8201a, RC48-ADC) and other novel therapies (e.g., ZW25, CAR-T, BVAC-B). In this study, we will summarize the recent advances in anti-HER-2 agents, potential mechanisms of resistance to HER2-targeted therapy in HER2-positive gastric cancer. We will also discuss the future prospects of potential strategies to overcome anti-HER-2 resistance and development of novel anti-HER-2 approaches for the treatment of HER2-positive gastric cancer patients.

2.
Medicine (Baltimore) ; 100(16): e25342, 2021 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-33879663

RESUMO

BACKGROUND: The incidence of malnutrition in patients with esophageal cancer is high, which seriously affects the therapeutic effect and quality of life. Oral nutritional supplement is the first choice of nutritional support recommended by current guidelines, which can supplement the lack of energy and protein in patients with esophageal cancer, improve nutritional status and improve the quality of life, but there are few clinical studies. Therefore, the purpose of this randomized controlled trial is to evaluate the effect of oral nutritional supplement therapy on nutritional status and quality of life in patients with esophageal cancer treated undergoing radiotherapy and chemotherapy. METHODS: This is a prospective randomized controlled trial to study the effects of oral nutritional supplement therapy on nutritional status and quality of life in patients with esophageal cancer undergoing radiotherapy and chemotherapy. This study is approved by the Clinical Research Society of our hospital. Patients will be randomly divided into ONS group and traditional diet group. The nutritional status, quality of life score and adverse reactions will be observed before and after radiotherapy and chemotherapy. The data will be analyzed by SPSS 16.0. DISCUSSION: This study will evaluate the effect of oral nutritional supplement therapy on nutritional status and quality of life of patients with esophageal cancer undergoing radiotherapy and chemotherapy. The results of this experiment will establish clinical evidence for the application of oral nutritional supplement therapy in patients with esophageal cancer undergoing radiotherapy and chemotherapy. OSF REGISTRATION NUMBER: DOI 10.17605/OSF.IO/9ZW34.


Assuntos
Quimiorradioterapia/efeitos adversos , Suplementos Nutricionais , Neoplasias Esofágicas/terapia , Desnutrição/prevenção & controle , Apoio Nutricional/métodos , Adulto , Neoplasias Esofágicas/complicações , Neoplasias Esofágicas/fisiopatologia , Feminino , Humanos , Masculino , Desnutrição/etiologia , Pessoa de Meia-Idade , Estado Nutricional , Estudos Prospectivos , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
3.
Reproduction ; 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33784242

RESUMO

Preeclampsia is a gestational hypertensive disease; however, preeclampsia remains poorly understood. Bioinformatics analysis was applied to find novel genes involved in the pathogenesis of preeclampsia and identified CLDN1 as one of the most differentially expressed genes when comparing patients with preeclampsia and healthy controls. The results of the qRT-PCR, western blotting and immunohistochemistry experiments demonstrated that CLDN1 was significantly downregulated in the chorionic villi in samples from patients with preeclampsia. Furthermore, knockdown of CLDN1 in HTR-8/SVneo cells resulted in the inhibition of proliferation and induction of apoptosis, and overexpression of CLDN1 reversed these effects. In addition, RNA-seq assays demonstrated that the gene BIRC3 is potentially downstream of CLDN1 and is involved in the regulation of apoptosis. Knockdown of CLDN1 confirmed that the expression level of BIRC3 was obviously decreased and was associated with a significant increase in cleaved PARP. Interestingly, the apoptotic effect in CLDN1 knockdown cells was rescued after BIRC3 overexpression. Overall, these results indicate that a decrease in CLDN1 inhibits BIRC3 expression and increases cleaved PARP levels thus participating in the pathogenesis of preeclampsia.

4.
EBioMedicine ; 65: 103253, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33639402

RESUMO

BACKGROUND: Congenital malformations are common birth defects with high neonatal morbidity and mortality. It is essential to find simpler and more efficient biomarkers for early prenatal diagnosis. Therefore, we investigated PIWI-interacting RNAs (piRNAs) as potential prenatal biomarkers in plasma-derived exosomes from pregnant women carrying foetuses with congenital malformations. METHODS: Small RNA sequencing was used to screen piRNA biomarkers in plasma-derived exosomes of five pregnant women carrying foetuses with nonsyndromic cleft lip and palate (nsCLP) and five women carrying normal foetuses. Differentially expressed piRNAs were verified in 270 pregnant women, including 111 paired women carrying foetuses with congenital malformations and normal foetuses (at 24 gestational weeks), 10 paired women carrying foetuses with nsCLP and normal foetuses (at 15-19 gestational weeks), and 28 women at different stages of normal pregnancy. piRNA biomarkers were also verified in placentas, umbilical cords, fetal medial calf muscles, and lip tissues of nsCLP and normal foetuses. FINDINGS: We identified a biomarker panel of three pregnancy-associated exosomal piRNAs (hsa-piR-009228, hsa-piR-016659, and hsa-piR-020496) could distinguish nsCLP foetuses from normal foetuses. These three piRNAs had better diagnostic accuracy for nsCLP at the early gestational stage, at which time typical malformations were not detected upon prenatal ultrasound screening, and had diagnostic value for neural tube defects (NTDs) and congenital heart defects (CHDs). INTERPRETATION: Our work revealed the potential clinical applications of piRNAs for predicting nsCLP, NTDs, and CHDs. FUNDING: National Key Research and Development Program, National Natural Science Foundation of China, and LiaoNing Revitalization Talents Program .

5.
Nutrition ; 81: 110896, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32739657

RESUMO

OBJECTIVES: Developmental dysplasia of the hip (DDH) is one of the most common orthopedic birth defects in newborn infants, for whom early detection and treatment are critical. MiR-140 plays an important role in bone development and was found to be regulated by vitamin D receptors in our previous study. This study aimed to investigate vitamin D status and miR-140 expression in the circulation of patients with orthopedic conditions, including DDH. METHODS: The 25-hydroxyvitamin D (25[OH]D) status and miR-140 expression were determined in the serum of 120 patients with orthopedic conditions. Receiver operating characteristic curves were used to evaluate the potential diagnosis capability of 25(OH)D status and miR-140 expression in DDH. A DDH rat model was also used to verify miR-140 expression in vivo. RESULTS: We found that most patients with orthopedic conditions have vitamin D insufficiency and deficiency, and patients with DDH are in the insufficiency range. MiR-140 was downregulated in the serum of patients with DDH patients and in the hip joints of rats with DDH. A panel of 25(OH)D and miR-140 showed robust performance in distinguishing DDH from controls. CONCLUSIONS: Our results indicate that miR-140 may play an important role in DDH, with the potential capability of being a biomarker for the diagnosis of DDH.

6.
Stem Cell Res Ther ; 11(1): 480, 2020 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-33176873

RESUMO

BACKGROUND: Nontraumatic osteonecrosis of the femoral head (NONFH) is a highly disabling orthopedic disease in young individuals. Plasminogen activator inhibitor 1 (PAI-1) has been reported to be positively associated with NONFH. We aimed to investigate the dysregulating PAI-1 in bone marrow mesenchymal stem cells (BMMSCs) and vascular cells in rabbit steroid-induced NONFH. METHODS: To verify the hypothesis that BMMSCs could promote thrombus formation in a paracrine manner, we collected exosomes from glucocorticoid-treated BMMSCs (GB-Exo) to determine their regulatory effects on vascular cells. microRNA sequencing was conducted to find potential regulators in GB-Exo. Utilizing gain-of-function and knockdown approaches, we testified the regulatory effect of microRNA in exosomes. RESULTS: The expression of PAI-1 was significantly increased in the local microenvironment of the femoral head in the ONFH model. GB-Exo promoted PAI-1 expression in vascular smooth muscle cells and vascular endothelial cells. We also revealed that miR-451-5p in GB-Exo plays a crucial role for the elevated PAI-1. Moreover, we identified miR-133b-3p and tested its role as a potential inhibitor of PAI-1. CONCLUSIONS: This study provided considerable evidence for BMMSC exosomal miR-mediated upregulation of the fibrinolytic regulator PAI-1 in vascular cells. The disruption of coagulation and low fibrinolysis in the femoral head will eventually lead to a disturbance in the microcirculation of NONFH. We believe that our findings could be of great significance for guiding clinical trials in the future.

7.
PLoS One ; 15(11): e0238709, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33151946

RESUMO

Changes in precipitation patterns greatly impact regional drought/flood risk management and utilization of water resources. The main purpose of this paper was to investigate spatio-temporal variability of precipitation concentration in the transitional zone between Qinling Mountains (QDM), Guanzhong Plain (GZP) and the Loess Plateau (LPNS) in China, using monthly-scale precipitation concentration index (PCI) and daily-scale concentration index (CI) from daily rainfall records. The Mann-Kendall method was employed to illustrate the change in trend of PCI and CI, the Kriging interpolation method was adopted to measure spatial distribution, and the Wavelet transforms were used to explore their spatio-temporal correlation with the Arctic Oscillation (AO) & Western Pacific Subtropical High (WPSH) for revealing the potential attribution of precipitation concentration variation. Also, the regional implication of CI was investigated in the zone to provide local knowledge of the index application. Results showed that annual precipitation demonstrated a north-south increasing layered spatial distribution in the zone, representing a generally decreasing trend. The CI change generally exhibited a more significant decreasing trend than did PCI in LPNS and GZP due to AO slowly increasing over time, with a spatially weak layered or radial north-south decay, and an insignificant increasing trend in QDM impacted by the enhancing WPSH, with an obvious layered or radial spatial distribution. The spatiotemporal pattern of PCI variation represented similar characteristics in attribution with CI, but an inverse spatial distribution due to the phase difference (positive and negative effects) of AO and WPSH influencing seasonal precipitation. Regional analysis of CI showed that the CI value with over 0.62 indicated that approximately 80% of precipitation was contributed by 25% of the rainiest days in this zone. Fortunately, the area with this high CI has been getting smaller, implying a positive trend toward regional flash flood and debris flow control.

8.
Cell Oncol (Dordr) ; 43(6): 1049-1066, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33006750

RESUMO

PURPOSE: Stemming from a myriad of genetic and epigenetic alterations, triple-negative breast cancer (TNBC) is tied to poor clinical outcomes and aspires for individualized therapies. Here we investigated the therapeutic potential of co-inhibiting integrin-dependent signaling pathway and BRD4, a transcriptional and epigenetic mediator, for TNBC. METHODS: Two independent patient cohorts were subjected to bioinformatic and IHC examination for clinical association of candidate cancer drivers. The efficacy and biological bases for co-targeting these drivers were interrogated using cancer cell lines, a protein kinase array, chemical inhibitors, RNAi/CRISPR/Cas9 approaches, and a 4 T1-Balb/c xenograft model. RESULTS: We found that amplification of the chromosome 8q24 region occurred in nearly 20% of TNBC tumors, and that it coincided with co-upregulation or amplification of c-Myc and FAK, a key effector of integrin-dependent signaling. This co-upregulation at the mRNA or protein level correlated with a poor patient survival (p < 0.0109 or p < 0.0402, respectively). Furthermore, we found that 14 TNBC cell lines exhibited high vulnerabilities to the combination of JQ1 and VS-6063, potent pharmacological antagonists of the BRD4/c-Myc and integrin/FAK-dependent pathways, respectively. We also observed a cooperative inhibitory effect of JQ1 and VS-6063 on tumor growth and infiltration of Ly6G+ myeloid-derived suppressor cells in vivo. Finally, we found that JQ1 and VS-6063 cooperatively induced apoptotic cell death by altering XIAP, Bcl2/Bcl-xl and Bim levels, impairing c-Src/p130Cas-, PI3K/Akt- and RelA-associated signaling, and were linked to EMT-inducing transcription factor Snail- and Slug-dependent regulation. CONCLUSION: Based on our results, we conclude that the BRD4/c-Myc- and integrin/FAK-dependent pathways act in concert to promote breast cancer cell survival and poor clinical outcomes. As such, they represent promising targets for a synthetic lethal-type of therapy against TNBC.

9.
In Vitro Cell Dev Biol Anim ; 56(9): 701-714, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33029689

RESUMO

Amniotic fluid (AF) is a rich source of mesenchymal stromal cells (MSCs) that have the ability to differentiate into multiple lineages rendering them a promising and powerful tool for regenerative medicine. However, information regarding the differences among AFMSCs derived from different gestational stages is limited. In the present study, AFMSCs derived from 125 pregnant rats at four embryonic day (E) stages (E12, E15, E18, and E21) were isolated and cultured. The primary E15 cells were the smallest in size and the easiest to culture and usually grew in a spherical shape that resembled the growth morphology of embryonic stem cells (ESCs). Once adhered, the E12 and E15 AFMSCs grew faster and could be passaged more than 60 times while still maintaining a continuous proliferative state; however, AFMSCs derived from E18 and E21 could normally be maintained for only 10 passages. To identify the possible reasons for this difference, RT-qPCR was used to examine several genes associated with self-renewal ability and cell origin. The Sox2 expression levels indicated that AFMSCs from E12 and E15 possessed stronger self-renewal capability. The K19, Col2A1, FGF5, AFP, and SPC expression levels indicated there were mixed-population cells co-existing in the AFMSC culture. In conclusion, E15 cells were easier to culture than E12 cells, could be passaged more often, and had a higher Sox2 expression than E18 or E21 cells. The E15-derived AFMSCs had higher viability and proliferative capacity than cells from the later stages. Therefore, AF cells from the early stages could be a good choice for exploring potential treatments involving AFMSCs.

10.
Front Cell Dev Biol ; 8: 652, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32793596

RESUMO

We investigated the therapeutic potential of targeting integrin/FAK-dependent signaling, an adhesion receptor-mediated pathway that has been increasingly linked to non-small cell lung cancer (NSCLC) malignancy. Our analysis of the TCGA cohort showed that a subset of pro-tumorigenic integrins, including α1ß1, α2ß1, α3ß1, α5ß1, and α6ß4, were frequently amplified or upregulated at the genomic or mRNA level in KRAS or EGFR mutation/overexpression-enriched adenocarcinomas. These alterations appeared complementary, correlated with poor patient survival (p < 0.0072), and were collaborative with KRAS mutation-coupled αv integrins (p < 0.00159). Since integrin/FAK-dependent signaling is tightly coupled with normal human physiology, we sought to use a synthetic lethal-type targeting comprising of VS-6063, a chemical inhibitor of integrin-mediated FAK activity, and A549 cells, which carry a KRAS mutation and EGFR overexpression. Our screening analysis revealed that JQ1 and IBET-762, inhibitors of epigenetic reader BRD4, and LBH589, a pan inhibitor of histone deacetylases (HDACs), exhibited synergy with VS-6063 in mitigating tumor cell viability. This epigenetic link was corroborated by strong effects of additional inhibitors and RNAi-mediated knockdown of FAK and BRD4 or its downstream effector, c-Myc. Low doses of JQ1 (≤0.5 µM) markedly escalated efficacy of VS-6063 across a panel of 10 NSCLC cell lines. This catalyst-like effect is in line with the oncogenic landscape in the TCGA cohort since c-Myc falls downstream of the KRAS and EGFR oncogenes. Mechanistically, co-inhibiting the integrin-FAK and BRD4/c-Myc axes synergistically induced apoptotic cell death and DNA damage response, and impaired stemness-associated tumorsphere formation. These effects were accompanied by a marked inhibition of Akt- and p130Cas/Src-dependent signaling, but not Erk1/2 activity. Meanwhile, JQ1 alone or in combination with VS-6063 attenuated cell-cell adhesion and extracellular matrix (ECM)-dependent cell spreading, which is reminiscent of phenotype induced by malfunctional E-cadherin or integrins. Paradoxically, this phenotypic impact coincided with downregulation of epithelial-mesenchymal transition (EMT)-inducting transcription factor ZEB1 or Snail. Finally, we showed that the effect of the VS-6063/JQ1 combination was nearly equivalent to that of VS-6063 plus Carboplatin or Osimertinib. Overall, our study indicates that the integrin/FAK and BRD4/c-Myc axes cooperatively drive NSCLC virulence, and a co-targeting may provide a line of therapy capable of overcoming EGFR/KRAS-driven malignancy.

11.
Ann N Y Acad Sci ; 1478(1): 75-91, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32761624

RESUMO

Neural tube defects (NTDs) are serious congenital malformations. In this study, we aimed to identify more specific and sensitive maternal serum biomarkers for noninvasive NTD screenings. We collected serum from 37 pregnant women carrying fetuses with NTDs and 38 pregnant women carrying normal fetuses. Isobaric tags for relative and absolute quantitation were conducted for differential proteomic analysis, and an enzyme-linked immunosorbent assay was used to validate the results. We then used a support vector machine (SVM) classifier to establish a disease prediction model for NTD diagnosis. We identified 113 differentially expressed proteins; of these, 23 were either up- or downregulated 1.5-fold or more, including five complement proteins (C1QA, C1S, C1R, C9, and C3); C3 and C9 were downregulated significantly in NTD groups. The accuracy rate of the SVM model of the complement factors (including C1QA, C1S, and C3) was 62.5%, with 60% sensitivity and 67% specificity, while the accuracy rate of the SVM model of alpha-fetoprotein (AFP, an established biomarker for NTDs) was 62.5%, with 75% sensitivity and 50% specificity. Combination of the complement factor and AFP data resulted in the SVM model accuracy of 75%, and receiver operating characteristic curve analysis showed 75% sensitivity and 75% specificity. These data suggest that a disease prediction model based on combined complement factor and AFP data could serve as a more accurate method of noninvasive prenatal NTD diagnosis.

12.
Cell Death Dis ; 11(7): 523, 2020 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-32655141

RESUMO

Neural tube defects (NTDs) lead to prenatal mortality and lifelong morbidity. Currently, surgical closure of NTD lesions results in limited functional recovery. We previously suggested that nerve regeneration was critical for NTD therapy. Here, we report that transamniotic bone marrow-derived mesenchymal stem cell (BMSC) therapy for NTDs during early development may achieve beneficial functional recovery. In our ex vivo rat embryonic NTD model, BMSCs injected into the amniotic cavity spontaneously migrated into the defective neural tissue. Hepatocyte growth factor and its receptor c-MET were found to play critical roles in this NTD lesion-specific migration. Using the in vivo rat fetal NTD model, we further discovered that the engrafted BMSCs specifically differentiated into the cell types of the defective tissue, including skin and different types of neurons in situ. BMSC treatment triggered skin repair in fetuses, leading to a 29.9 ± 5.6% reduction in the skin lesion area. The electrophysiological functional recovery assay revealed a decreased latency and increased motor-evoked potential amplitude in the BMSC-treated fetuses. Based on these positive outcomes, ease of operation, and reduced trauma to the mother and fetus, we propose that transamniotic BMSC administration could be a new effective therapy for NTDs.

13.
Cancer Med ; 9(16): 6009-6019, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32627968

RESUMO

Bladder Cancer (BC) is the ninth most common tumor in the world and one of the most common malignant tumors of the urinary system. Some studies reported that miR-133b expression is reduced in BC, but whether it plays a role in the development of BC and its mechanism is unclear. microRNAs can be packaged into exosomes to mediate communication between tumor cells, affecting their proliferation and apoptosis. The objective of this study was to investigate the effect of exosomal miR-133b on BC proliferation and its molecular mechanism. Firstly, the expression of miR-133b was evaluated in BC and adjacent normal tissues, as well as in serum exosomes of BC patients and healthy controls. Then the delivery and internalization of exosomes in cells was observed through fluorescence localization. Cell viability and apoptosis were assessed in BC cells transfected with mimics and incubated with exosomes. The role of exosomal miR-133b was also analyzed in nude mice transplant tumors. Furthermore, the target gene of miR-133b was predicted through bioinformatics. The level of miR-133b was significantly decreased in BC tissues and in exosomes from serum of patients, which was correlated with poor overall survival in TCGA. Exosomal miR-133b could be obtained using BC cells after transfection with miR-133b mimics. The miR-133b expression increased after incubation with exosomal miR-133b, which lead to the inhibition of viability and increase of apoptosis in BC cells. Exosomal miR-133b could suppress tumor growth in vivo. In addition, we found that exosomal miR-133b may play a role in suppressing BC proliferation by upregulating dual-specificity protein phosphatase 1 (DUSP1). These findings may offer promise for new therapeutic directions of BC.

14.
J Biomed Mater Res B Appl Biomater ; 108(7): 2925-2936, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32662233

RESUMO

Zn alloys are emerging as promising degradable biomedical materials due to their tailorable mechanical properties and moderate biodegradable rate, compared with conventional biodegradable metallic materials. Ag, as an effective antibacterial and reinforcing element, was incorporated into Zn-0.05Mg alloys. In the present work, the effects of the Ag addition on mechanical, cytotoxic, hemolytic, pyrogenic, histological behaviors of the animal were investigated. The compressive yielding strength is enhanced from 198 MPa for Zn-0.05Mg alloy up to 224 and 234 MPa for Zn-0.05Mg-0.5Ag and Zn-0.05Mg-1Ag alloys, respectively. When the compressive strain was 65%, the strength of the Zn-0.05Mg-1.0Ag alloy reached 833 MPa, which was much higher than that of 721 MPa for Zn-0.05Mg alloy. The relative growth rate (RGR) for the extracts of Zn-0.05Mg-1Ag alloy with the concentrations of 10, 50, and 100% after 5 days incubation reaches 98.5, 95.2, and 94.2%, which are higher than those in extracts of Zn-0.05Mg-0.5Ag alloy (98.2, 93.9, 92.1%). The hemolysis rate of the Zn-0.05Mg alloys with 0.5 and 1 wt% Ag is 2.46 and 2.28%, respectively. The variations of body weight and temperature, postinjection symptoms, pathological morphologies of the visceral organs demonstrate that the alloys are nontoxic according to the toxicity rating standards. Zn-0.05wt%Mg-(0.5, 1 wt%) Ag alloys are experimentally safe materials and promising for the future application as biodegradable medical devices.

15.
Medicine (Baltimore) ; 99(25): e20809, 2020 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-32569228

RESUMO

RATIONALE: Pyrotinib is a novel dual pan-ErbB receptor tyrosine kinase inhibitor, approved for the treatment of human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC). However, there was still limited information regarding specific effect of pyrotinib on HER2-positive MBC patients with phosphoinositol-3 kinase mutation. PATIENT CONCERNS: A 63-year-old woman accidentally discovered a left breast lesion. The breast cancer was diagnosed by biopsy of breast lesion and postoperative pathological examination in March, 2017. The patient was presented with HER2-positive (3+), invasive carcinoma of the left breast with lymph nodes and lung nodules metastasis, and the clinical stage was T4N2M1. However, the lesion continued to aggressive disease progression with the treatment of trastuzumab plus multiple chemotherapy regimens and traditional Chinese medicine. DIAGNOSES: The woman was diagnosed with invasive carcinoma of the left breast and lymph nodes and lung nodules metastasis. INTERVENTIONS: The patient received 6 cycles of pyrotinib in combination with capecitabine regularly. OUTCOMES: Progression free survival was more than 6 months, and the patient's efficacy evaluation was partial remission. LESSONS: Our clinical observations demonstrated that pyrotinib may be an effective treatment for patients with HER2-positive MBC.


Assuntos
Acrilamidas/uso terapêutico , Aminoquinolinas/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Carcinoma Ductal de Mama/tratamento farmacológico , Receptor ErbB-2/antagonistas & inibidores , Acrilamidas/administração & dosagem , Aminoquinolinas/administração & dosagem , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Capecitabina/administração & dosagem , Capecitabina/uso terapêutico , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/patologia , Feminino , Humanos , Pessoa de Meia-Idade
16.
Clin Exp Med ; 20(3): 437-447, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32514710

RESUMO

To investigate lncRNAs acting as competing endogenous RNAs (ceRNAs) involved in oncogenesis and progression of HCC. Different expressed lncRNAs, microRNAs, and mRNAs (DElncRNAs, DEmiRNAs, DEmRNAs), downloaded from The Cancer Genome Atlas (TCGA) database, were identified by edgeR package. CeRNA network was constructed based on miRcode, TargetScan, and miRTarBase. Target DEmRNAs were annotated by KEGG pathway and GO analysis. Negatively correlated lncRNA-miRNA pairs were analyzed by Pearson correlation coefficient, simultaneously, overall survival (OS) were evaluated. The expression of these lncRNAs were examined in HCC cell lines and tissues through qRT-PCR. 1070 DElncRNAs, 147 DEmiRNAs and 1993 DEmRNAs were acquired. CeRNA network was successfully established, including 27 lncRNAs, 5 miRNAs, and 30 mRNAs significantly correlated with OS. The DEmRNAs were significantly enriched in "Cell Cycle" and "pathways in cancer". Six lncRNAs and 2 miRNAs were negatively correlated. These lncRNAs were validated by qRT-PCR. These observations will provide a novel perspective to elucidate HCC pathogenesis.

17.
Am J Transl Res ; 12(4): 1428-1442, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32355552

RESUMO

Owing to the complexity of interacting molecular networks on the cell surface, integrin-associated tetraspanin CD151 remains controversial regarding its clinical importance and functional impact in prostate cancer. The current study evaluated dynamics and clinical importance of CD151 expression and its function in prostate cancer by IHC analysis of two independent patient cohorts (n=80, 181), bioinformatic interrogation of the TCGA database, and evaluation of gene knockdown effect at the cellular level. Our data showed that aside from high mRNA expression, CD151 was primarily localized to intercellular junctions at the plasma membrane in normal prostate glands or benign tissues, regardless of nature of antibodies used. By contrast, in primary tumors from patients with metastatic disease, CD151 was largely localized in the cytosol. Furthermore, the level of the cell-cell junction-linked CD151 was inversely associated with Gleason grade and tumor stage (P<0.001 for both). The portion of primary tumors expressing junctional CD151 was also three-fold less in the metastatic patient population than its counterpart (P<0.001). In line with these observations, CD151 and its associated α3ß1 or α6ß4 integrin inversely correlated with androgen receptor (AR) at the mRNA level (Spearman coefficient: -0.44, -0.48 and -0.42) in the TCGA cohort. Expression of these adhesion molecules also correlated with DNA methylation in their promoters (Spearman coefficient: -0.37, -0.71 and -0.82). Combined, these data suggest that CD151 and associated integrins are linked to tumor metastasis through AR and the epigenetic program. Meanwhile, CD151 knockdown in E-cadherin-positive tumor cells led to increased cell proliferation and induction of the epithelial-mesenchymal transition (EMT)-like phenotype. Given the strong RGD-binding integrin dependence of EMT-featured tumor cells, we examined focal adhesion kinase (FAK), their key signaling effector, in the above patient cohorts. In contrast to CD151, FAK exhibited positive correlation with tumor grade and stage as well as AR and p53 inactivation at either mRNA, protein or genomic level. Taken together, our results suggest that CD151 represses prostate cancer by antagonizing cell proliferation, EMT and the signaling of RGD-binding integrins. Since this anti-tumorigenic role is prone to the AR-mediated transcriptional and epigenetic regulation, CD151 and possibly α3ß1 and α6ß4 integrins are of potential biomarkers for metastatic prostate cancer.

18.
Biochem Biophys Res Commun ; 527(1): 187-193, 2020 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-32446365

RESUMO

BACKGROUND: Amniotic fluid-derived mesenchymal stromal cells (AFMSCs) are promising stem cells for regeneration medicine. However, AFMSCs isolated at different stages of pregnancy have different biological characteristics, and the therapeutic effects can differ in vivo and in vitro. The mechanisms underlying these differences have not been defined. METHODS: Bioinformatics analysis of the AFMSC transcriptome identified Chrdl1 as one of the differentially expressed genes. We evaluated the effects of Chrdl1 overexpression or knockdown on the proliferation and migration of AFMSCs. Target prediction was performed using miRanda software to identify the upstream microRNA of Chrdl1. The interaction between Chrdl1 mRNA and its upstream microRNA was evaluated using a dual-luciferase reporter gene assay. RESULTS: Chrdl1 was expressed at lower levels in AFMSCs derived from the early stages of pregnancy. It could suppress AFMSC proliferation and migration. miR-532-3p promoted AFMSC proliferation and migration by targeting the 3' UTR of Chrdl1 and downregulating its expression.

20.
Int J Oncol ; 56(5): 1064-1074, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32319568

RESUMO

Prostate cancer (PCa) and breast cancer (BCa) are two common sex hormone­related cancer types with high rates of morbidity, and are leading causes of cancer death globally in men and women, respectively. The biological function of androgen or estrogen is a key factor for PCa or BCa tumorigenesis, respectively. Nevertheless, after hormone deprivation therapy, the majority of patients ultimately develop hormone­independent malignancies that are resistant to endocrinotherapy. It is widely recognized, therefore, that understanding of the mechanisms underlying the process from hormone dependence towards hormone independence is critical to discover molecular targets for the control of advanced PCa and BCa. This review aimed to dissect the important mechanisms involved in the therapeutic resistance of PCa and BCa. It was concluded that activation of the NF­κB pathway is an important common mechanism for metastasis and therapeutic resistance of the two types of cancer; in particular, the RelB­activated noncanonical NF­κB pathway appears to be able to lengthen and strengthen NF­κB activity, which has been a focus of recent investigations.

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