Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 87
Filtrar
1.
Clin Transl Med ; 12(5): e825, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35522895

RESUMO

AIMS: MORC family CW-type zinc finger 2 (MORC2), a GHKL-type ATPase, is aberrantly upregulated in multiple types of human tumors with profound effects on cancer aggressiveness, therapeutic resistance, and clinical outcome, thus making it an attractive drug target for anticancer therapy. However, the antagonists of MORC2 have not yet been documented. METHODS AND RESULTS: We report that MORC2 is a relatively stable protein, and the N-terminal homodimerization but not ATP binding and hydrolysis is crucial for its stability through immunoblotting analysis and Quantitative real-time PCR. The N-terminal but not C-terminal inhibitors of heat shock protein 90 (HSP90) destabilize MORC2 in multiple cancer cell lines, and strikingly, this process is independent on HSP90. Mechanistical investigations revealed that HSP90 N-terminal inhibitors disrupt MORC2 homodimer formation without affecting its ATPase activities, and promote its lysosomal degradation through the chaperone-mediated autophagy pathway. Consequently, HSP90 inhibitor 17-AAG effectively blocks the growth and metastatic potential of MORC2-expressing breast cancer cells both in vitro and in vivo, and these noted effects are not due to HSP90 inhibition. CONCLUSION: We uncover a previously unknown role for HSP90 N-terminal inhibitors in promoting MORC2 degradation in a HSP90-indepentent manner and support the potential application of these inhibitors for treating MORC2-overexpressing tumors, even those with low or absent HSP90 expression. These results also provide new clue for further design of novel small-molecule inhibitors of MORC2 for anticancer therapeutic application.


Assuntos
Antineoplásicos , Neoplasias da Mama , Fatores de Transcrição , Adenosina Trifosfatases/genética , Antineoplásicos/farmacologia , Autofagia/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Feminino , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Proteínas de Choque Térmico HSP90/genética , Humanos , Proteínas Oncogênicas
2.
J Hematol Oncol ; 15(1): 45, 2022 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-35477416

RESUMO

Targeting nucleotide metabolism can not only inhibit tumor initiation and progression but also exert serious side effects. With in-depth studies of nucleotide metabolism, our understanding of nucleotide metabolism in tumors has revealed their non-proliferative effects on immune escape, indicating the potential effectiveness of nucleotide antimetabolites for enhancing immunotherapy. A growing body of evidence now supports the concept that targeting nucleotide metabolism can increase the antitumor immune response by (1) activating host immune systems via maintaining the concentrations of several important metabolites, such as adenosine and ATP, (2) promoting immunogenicity caused by increased mutability and genomic instability by disrupting the purine and pyrimidine pool, and (3) releasing nucleoside analogs via microbes to regulate immunity. Therapeutic approaches targeting nucleotide metabolism combined with immunotherapy have achieved exciting success in preclinical animal models. Here, we review how dysregulated nucleotide metabolism can promote tumor growth and interact with the host immune system, and we provide future insights into targeting nucleotide metabolism for immunotherapeutic treatment of various malignancies.


Assuntos
Imunoterapia , Neoplasias , Animais , Humanos , Fatores Imunológicos/uso terapêutico , Neoplasias/tratamento farmacológico , Nucleotídeos/uso terapêutico
3.
Molecules ; 27(6)2022 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-35335248

RESUMO

Imidazole and tetrazole derivatives are widely used as clinical drugs since they possess a variety of pharmaceutical function. Zinc and iron are essential trace elements of the human body, with less toxicity and good biocompatibility. In this paper, two new essential metal mononuclear complexes [M(H2tmidc)2(H2O)2]·2H2O (M = Zn (1), Fe (2)) were synthesized through the reaction of 2-((1H-tetrazol-1-yl)methylene)-1H-imidazole-4,5-dicarboxylic acid (H3tmidc) and ZnSO4·7H2O or FeSO4·7H2O. The crystal structures were determined by means of the X-ray single crystal diffraction technique. Results from fluorescence investigations show that both complexes could interact with BSA as well as HSA through the static quenching mechanism. van der Waals forces and hydrogen bonds play important roles in the interaction of complexes and BSA/HSA since both ΔH and ΔS values are negative. The results of molecular docking are consistent with those in experimental studies. Furthermore, the anticancer activity of H3tmidc and both complexes against Eca-109 were preliminarily evaluated and the results show that both complexes have better anticancer activity than the corresponding ligand H3tmidc.


Assuntos
Complexos de Coordenação , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Humanos , Ligantes , Simulação de Acoplamento Molecular , Ligação Proteica , Termodinâmica
4.
Clin Cancer Res ; 2022 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-35247906

RESUMO

PURPOSE: Camrelizumab, a monoclonal antibody against PD-1, plus nab-paclitaxel exhibited promising antitumor activity in refractory metastatic immunomodulatory triple-negative breast cancer (TNBC). Famitinib is a tyrosine kinase inhibitor targeting VEGFR2, PDGFR and c-kit. We aimed to assess the efficacy and safety of a novel combination of famitinib, camrelizumab and nab-paclitaxel in advanced immunomodulatory TNBC. PATIENTS AND METHODS: This open-label, single-arm, phase II study enrolled patients with previously untreated, advanced, immunomodulatory TNBC (CD8 immunohistochemical staining {greater than or equal to} 10%). Eligible patients received 20 mg of oral famitinib on days 1-28, 200 mg of intravenous camrelizumab on days 1 and 15, and intravenous nab-paclitaxel 100 mg/m2 on days 1, 8 and 15 in 4-week cycles. The primary endpoint was objective response rate (ORR), as assessed by investigators per RECIST v1.1. Key secondary endpoints were progression-free survival (PFS), overall survival (OS), duration of response (DOR), safety and exploratory biomarkers. RESULTS: Forty-eight patients were enrolled and treated. Median follow-up was 17.0 months (range, 8.7-24.3). Confirmed ORR was 81.3% (95% CI, 70.2-92.3), with 5 complete and 34 partial responses. Median PFS was 13.6 months (95% CI, 8.4-18.8), and median DOR was 14.9 months (95% CI, NE-NE). Median OS was not reached. No treatment-related deaths were reported. Among 30 patients with immunohistochemistry, 13 (43.3%) were PD-L1-positive, and PD-L1 was associated with favorable response. PKD1 and KAT6A somatic mutations were associated with therapy response. CONCLUSIONS: The triplet regimen was efficacious and well tolerated in previously untreated, advanced, immunomodulatoryTNBC. The randomized controlled FUTURE-SUPER trial is underway to validate our findings.

5.
Cell Death Differ ; 29(4): 861-873, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34974534

RESUMO

MORC family CW-type zinc finger 2 (MORC2) is a newly identified chromatin-remodeling enzyme involved in DNA damage response and gene transcription, and its dysregulation has been linked with Charcot-Marie-Tooth disease, neurodevelopmental disorder, and cancer. Despite its functional importance, how MORC2 is regulated remains enigmatic. Here, we report that MORC2 is O-GlcNAcylated by O-GlcNAc transferase (OGT) at threonine 556. Mutation of this site or pharmacological inhibition of OGT impairs MORC2-mediated breast cancer cell migration and invasion in vitro and lung colonization in vivo. Moreover, transforming growth factor-ß1 (TGF-ß1) induces MORC2 O-GlcNAcylation through enhancing the stability of glutamine-fructose-6-phosphate aminotransferase (GFAT), the rate-limiting enzyme for producing the sugar donor for OGT. O-GlcNAcylated MORC2 is required for transcriptional activation of TGF-ß1 target genes connective tissue growth factor (CTGF) and snail family transcriptional repressor 1 (SNAIL). In support of these observations, knockdown of GFAT, SNAIL or CTGF compromises TGF-ß1-induced, MORC2 O-GlcNAcylation-mediated breast cancer cell migration and invasion. Clinically, high expression of OGT, MORC2, SNAIL, and CTGF in breast tumors is associated with poor patient prognosis. Collectively, these findings uncover a previously unrecognized mechanistic role for MORC2 O-GlcNAcylation in breast cancer progression and provide evidence for targeting MORC2-dependent breast cancer through blocking its O-GlcNAcylation.


Assuntos
Neoplasias da Mama , Fator de Crescimento Transformador beta1 , Neoplasias da Mama/patologia , Feminino , Humanos , N-Acetilglucosaminiltransferases/genética , N-Acetilglucosaminiltransferases/metabolismo , Treonina , Fatores de Transcrição/genética
6.
Mil Med Res ; 9(1): 3, 2022 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-35012680

RESUMO

Bacteria can evolve rapidly by acquiring new traits such as virulence, metabolic properties, and most importantly, antimicrobial resistance, through horizontal gene transfer (HGT). Multidrug resistance in bacteria, especially in Gram-negative organisms, has become a global public health threat often through the spread of mobile genetic elements. Conjugation represents a major form of HGT and involves the transfer of DNA from a donor bacterium to a recipient by direct contact. Conjugative plasmids, a major vehicle for the dissemination of antimicrobial resistance, are selfish elements capable of mediating their own transmission through conjugation. To spread to and survive in a new bacterial host, conjugative plasmids have evolved mechanisms to circumvent both host defense systems and compete with co-resident plasmids. Such mechanisms have mostly been studied in model plasmids such as the F plasmid, rather than in conjugative plasmids that confer antimicrobial resistance (AMR) in important human pathogens. A better understanding of these mechanisms is crucial for predicting the flow of antimicrobial resistance-conferring conjugative plasmids among bacterial populations and guiding the rational design of strategies to halt the spread of antimicrobial resistance. Here, we review mechanisms employed by conjugative plasmids that promote their transmission and establishment in Gram-negative bacteria, by following the life cycle of conjugative plasmids.


Assuntos
Antibacterianos , Conjugação Genética , Antibacterianos/farmacologia , Conjugação Genética/genética , Farmacorresistência Bacteriana/genética , Transferência Genética Horizontal/genética , Humanos , Plasmídeos/genética
7.
Zhongguo Zhong Yao Za Zhi ; 46(21): 5450-5455, 2021 Nov.
Artigo em Chinês | MEDLINE | ID: mdl-34951195

RESUMO

Pharmacovigilance system is an extension of the original adverse drug reactions monitoring and reporting system as well as an internationally recognized basic system that must be matched with the whole life cycle supervision of drugs. European Union(EU)pharmacovigilance system, World Health Orgnization(WHO) Uppsala Monitoring Center system and ICH system are internationally recognized pharmacovigilance systems. They all have their own pharmacovigilance characteristics and could provide guarantee for clinical safe drug use. With the deepening of international communication, pharmacovigilance has also been developed in China. Pharmacovigilance of Chinese medicine is a new concept based on the existing pharmacovigilance system of chemical medicine and the characteristics of Chinese medicine. In ancient China, Chinese medicine also had its own ways of early warning. Ancient medical books have records on the toxicity classification, clinical pharmacovigilance and intoxication rescue of Chinese medicine. With the increase of public recognition of Chinese medicine in recent years, especially since the government issued the 13 th Five-Year Plan for the development of Chinese medicine, the pharmaceutical industry in China has paid more and more attention to the pharmacovigilance of Chinese medicine.However, the pharmacovigilance system of Chinese medicine has not yet been established, and it still needs to be explored and improved.Therefore, it is very necessary to develop the system to standardize pharmacovigilance-related activities of Chinese medicine. In this context, this study analyzed and learned the characteristics of pharmacovigilance systems of EU, ICH, and WHO Uppsala Monitoring Center, so as to provide some enlightenment for the establishment and improvement of pharmacovigilance system of Chinese medicine.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Farmacovigilância , Sistemas de Notificação de Reações Adversas a Medicamentos , Livros , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , União Europeia , Humanos , Medicina Tradicional Chinesa
8.
Front Oncol ; 11: 690658, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34527574

RESUMO

BACKGROUND: Loco-regional recurrences (LRR) following breast-conserving surgery (BCS) remain a heterogeneous class of disease that has significant variation in its biological behavior and prognosis. METHODS: To delineate the spatiotemporal patterns of LRR after BCS, we analyzed the data of 4325 patients treated with BCS from 2006 to 2016. Clinico-pathological and treatment specific factors were analyzed using the Cox proportional hazards model to identify factors predictive for LRR events. Recurrence patterns were scrutinized based on recurrence type and recurrence-free interval (RFI). Annual recurrence rates (ARR) were compared according to recurrence type and molecular subtype. RESULTS: With a median follow-up of 66 months, 120 (2.8%) LRRs were recorded as the first site of failure. Age, pathologic stage, and molecular subtype were identified as predictors of LRR. The major recurrence type was ipsilateral breast tumor recurrence, which mainly (83.6%) occurred ≤5y post surgery. In the overall population, ARR curves showed that relapse peaked in the first 2.5 years. Patients with regional nodal recurrence, shorter RFI, and synchronous distant metastasis were associated with a poorer prognosis. HER2-positive disease had a higher rate of LRR events, more likely to have in-breast recurrence, and had an earlier relapse peak in the first 2 years after surgery. CONCLUSIONS: LRR risk following BCS is generally low in Chinese ethnicity. Different recurrence patterns after BCS were related to distinct clinical outcomes. Management of LRR should be largely individualized and tailored to the extent of disease, the molecular profile of the recurrence, and to baseline clinical variables.

9.
Lancet Reg Health West Pac ; 11: 100158, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34327363

RESUMO

BACKGROUND: De-escalating anthracycline is gaining popularity for breast cancer patients. We aim to evaluate the non-inferiority of an anthracycline-free or short-term regimen to the standard anthracycline-based regimen for operable patients with human epidermal growth factor receptor 2 (HER2)-negative breast cancer. METHODS: It is a prospective, open-label, phase 3, randomized non-inferiority trial from June 1, 2010 to June 1, 2017. Follow-up had been kept until July 2019. This trial was conducted at Fudan University Shanghai Cancer Center. Patients with pT1-3N+ or pT2-3N0 but high-risk (grade II/III, lymphovascular invasion, ≤35 years of age or hormone-receptor negative) HER2-negative operable breast cancer were eligible and stratified by age, pathological tumour stage, pathological node status and hormone-receptor status. Patients were randomized to 6 cycles of docetaxel and cyclophosphamide (TC, n = 524), 3 cycles of cyclophosphamide/epirubicin/fluorouracil followed by 3 cycles of docetaxel (CEF-T, n = 523) or epirubicin and cyclophosphamide for 4 cycles followed by paclitaxel for 12 weeks (EC-P, n = 524) as the intention-to-treat population. Of these patients, 94% completed allocated therapy. Difference in disease-free survival (DFS) compared to EC-P. The prespecified non-inferiority margin was 4.5%, corresponding to the hazard ratio (HR) of 1.44 (one-sided α = 0.05), with an assumed 5-year DFS of 89% for EC-P. FINDINGS: Included in the intention-to-treat population were 1571 patients (median [IQR] age, 50 [45-57] years; 92% estrogen receptor [ER]-positive; 59% pN+). Through a median follow-up of 5.5 years, HR for TC versus EC-P was 1.05 (5-year DFS: 85.0% vs. 85.9%; 90% confidence interval [CI]: 0.79-1.39, non-inferior P = 0.048) and for CEF-T versus EC-P, 0.99 (5-year DFS: 85.1% vs. 85.9%; 90% CI: 0.75-1.30, non-inferior P = 0.045). Grade 3 or 4 adverse events for TC included rash (3.9%) and peripheral neuropathy (2.8%) and for CEF-T and EC-P diarrhea and nausea/vomiting were predominant. Results of per-protocol analyses were similar. INTERPRETATION: Both TC and CEF-T are non-inferior adjuvant regimen to EC-P mainly in patients with ER+HER2- breast cancer. TC is a safe regimen that avoids anthracycline-related side effects. FUNDING: This work was supported by grants from the National Natural Science Foundation of China (Grants 81672600, 81722032, 82072916, and 91959207), the 2018 Shanghai Youth Excellent Academic Leader, the Fudan ZHUOSHI Project, the Municipal Project for Developing Emerging and Frontier Technology in Shanghai Hospitals (grant SHDC12010116), the Cooperation Project of Conquering Major Diseases in the Shanghai Municipality Health System (grant 2013ZYJB0302), the Innovation Team of the Ministry of Education (grant IRT1223), and the Shanghai Key Laboratory of Breast Cancer (grant 12DZ2260100) and the National Cancer Institute (grant P30 CA16058).

10.
Breast Cancer Res Treat ; 185(2): 371-380, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32975708

RESUMO

PURPOSE: Resistance to paclitaxel remains a major challenge in treating breast cancer. Our preclinical study suggested that TEKT4 germline variations in breast cancer are associated with paclitaxel resistance and increase vinorelbine sensitivity. This clinical trial compared the efficacy of paclitaxel and vinorelbine in breast cancer neoadjuvant chemotherapy. METHODS: In this open-label, single-center, phase II trial, female patients with human epidermal growth factor receptor 2 (HER2)-negative, stage IIB-IIIC breast cancer harboring TEKT4 germline variations were randomly assigned to the paclitaxel plus epirubicin (PE) or vinorelbine plus epirubicin (NE). The primary endpoint was the pathologic complete response (pCR) rate, and the secondary endpoints were the objective response rate (ORR) and safety. Targeted sequencing of a panel comprising 484 breast-related genes was performed to identify pCR-associated somatic mutations in each group. RESULTS: 91 Patients were assigned to PE (46 patients) or NE (45 patients). NE numerically increased the pCR rate (22.2% versus 8.7%, P = 0.074). The ORRs for NE and PE were 82.2% and 76.1%, respectively. Interestingly, NE (15.4%) showed a significantly higher pCR rate than PE (0%) in the hormone receptor (HR)-positive subgroup (P = 0.044). Both regimens were well tolerated, with grade 3 and 4 toxicities reported at the expected levels. The biomarker analysis showed that UNC13D mutation predicted the pCR rate in NE (P = 0.011). CONCLUSIONS: Although the primary endpoint was not met, NE might bring clinical benefit to HR-positive patients or patients simultaneously carrying UNC13D mutations.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias da Mama , Epirubicina , Terapia Neoadjuvante , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Ciclofosfamida/uso terapêutico , Epirubicina/uso terapêutico , Feminino , Humanos , Proteínas de Membrana , Paclitaxel/efeitos adversos , Receptor ErbB-2/genética , Trastuzumab/uso terapêutico , Resultado do Tratamento , Vinorelbina/uso terapêutico
11.
J Natl Cancer Inst ; 113(7): 884-892, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-33151324

RESUMO

BACKGROUND: The germline variant spectrum of triple-negative breast cancer (TNBC) is different from that of other subtypes and has demonstrated ethnic differences. However, the germline variants of TNBC among Chinese patients and its clinical significance remain unclear. METHODS: Using our multi-omics TNBC cohort (n = 325), we determined the spectrum of germline variants in TNBC and aimed to illustrate their biological and clinical implications. RESULTS: Overall, 16.0% (52 of 325) of TNBC patients harbored at least 1 pathogenic or likely pathogenic germline variant. These germline variants were associated with early onset of TNBC, the occurrence of contralateral breast cancer, the basal-like immune-suppressed mRNA subtype, and the homologous recombination deficiency (HRD) mutation subtype. Somatic allele-specific imbalance was observed in 54.1% of these germline variants, which was correlated with early onset of breast cancer and elevated HRD. The genes BRCA1 (7.4%), RAD51D (2.8%), and BRCA2 (2.2%) were those most frequently mutated. The RAD51D germline variants, especially K91fs, were enriched in Chinese patients with TNBC compared with Caucasian and African American patients. The Chinese-specific RAD51D germline variants were functionally associated with the instability of the RAD51D protein, HRD, and sensitivity to PARP inhibitors. CONCLUSIONS: Chinese TNBC patients have a distinct spectrum of germline variants, with a remarkable impact on the clinical and molecular characteristics of the tumor. Integrative germline-somatic analysis may help identify TNBC patients who are most likely to be affected by their germline variants and in performing clinical interventions more precisely. The RAD51D variants enriched in our cohort may serve as therapeutic targets and guide precision treatment of TNBC.


Assuntos
Neoplasias de Mama Triplo Negativas , /genética , Proteína BRCA1/genética , Proteína BRCA2/genética , Células Germinativas/patologia , Mutação em Linhagem Germinativa , Humanos , Mutação , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/epidemiologia , Neoplasias de Mama Triplo Negativas/genética
12.
Front Oncol ; 11: 791995, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-35198434

RESUMO

INTRODUCTION: Locoregional recurrent breast cancer indicates poor prognosis. No solid prediction model is available to predict prognosis and guide clinical management. Prior local treatment or systemic treatment remains controversial. METHODS: Locoregional recurrent breast cancer patients operated in Fudan University Shanghai Cancer Center were enrolled as a training cohort. An external validation cohort included breast cancer patients after locoregional recurrence from Ruijin Hospital, Shanghai Jiaotong University. A nomogram predicting overall survival after locoregional recurrence was established using multivariable Cox regression analysis while internal and external validation were performed to evaluate its calibration and discrimination. RESULTS: Overall, 346 and 96 breast cancer patients were included in the training cohort and the validation cohort separately. A nomogram was developed, including age, neoadjuvant chemotherapy, breast surgery, pathology type, tumor size, lymph node status, hormonal receptor and Her-2 status, disease-free interval, and sites of locoregional recurrence. It had modest calibration and discrimination in the training cohort, internal validation and external validation (concordance index: 0.751, 0.734 and 0.722, respectively). The nomogram classified 266 and 80 patients into low and high-risk subgroups with distinctive prognosis. Local treatment after locoregional recurrence was associated with improved overall survival in low-risk group (P = 0.011), while systemic therapies correlated with better outcomes only in high-risk group (P < 0.001). CONCLUSION: A nomogram based on clinicopathological factors can predict prognosis and identify low and high-risk patients. Local treatment is a prior choice for low-risk patients whereas systemic treatment needs to be considered for high-risk patients, warranting further validation and exploration.

13.
Clin Transl Med ; 10(8): e245, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33377651

RESUMO

Pregnancy-specific glycoprotein 9 (PSG9) is a placental glycoprotein essential for the maintenance of normal gestation in mammals. Bioinformatics analysis of multiple publicly available datasets revealed aberrant PSG9 expression in breast tumors, but its functional and mechanistic role in breast cancer remains unexplored. Here, we report that PSG9 expression levels were elevated in tumor tissues and plasma specimens from breast cancer patients, and were associated with poor prognosis. Gain- or loss-of-function studies demonstrated that PSG9 promoted breast cancer cell proliferation, migration, and invasionin vitro, and enhanced tumor growth and lung colonization in vivo. Mechanistically, transforming growth factor-ß1 (TGF-ß1) transcriptionally activated PSG9 expression through enhancing the enrichment of Smad3 and Smad4 onto PSG9 promoter regions containing two putative Smad-binding elements (SBEs). Mutation of both SBEs in the PSG9 promoter, or knockdown of TGF-ß receptor 1 (TGFBR1), TGFBR2, Smad3, or Smad4 impaired the ability of TGF-ß1 to induce PSG9 expression. Consequently, PSG9 contributed to TGF-ß1-induced epithelial-mesenchymal transition (EMT) and breast cancer cell migration and invasion. Moreover, PSG9 enhanced the stability of Smad2, Smad3, and Smad4 proteins by blocking their proteasomal degradation, and regulated the expression of TGF-ß1 target genes involved in EMT and breast cancer progression, thus further amplifying the canonical TGF-ß/Smad signaling in breast cancer cells. Collectively, these findings establish PSG9 as a novel player in breast cancer progressionvia hijacking the canonical TGF-ß/Smad signaling, and identify PSG9 as a potential plasma biomarker for the early detection of breast cancer.

14.
Complement Ther Med ; 52: 102456, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32951717

RESUMO

OBJECTIVE: This study used a prospective cohort study to observe the effect of triple-negative breast cancer on the 2-year disease-free survival rate with or without "TCM formula". METHODS: From November 1 st, 2016, the first patient was enrolled in the cohort study. A total of 356 patients were enrolled on January 30, 2019. Among them, 154 cases were followed up for 2 years. During the follow-up, there were 6 cases of shedding, so 6 cases were affected. A total of 148 cases were included in the analysis, including 73 in the exposed group and 75 in the non-exposed group. The exposed group was given "TCM formula" on the basis of standardized treatment, and the non-exposed group was treated with simple triple-negative breast cancer. The two groups visited each of the three months. The interview included safety examination (hematology and imaging). The endpoint was the difference in 2-year invasive disease-free survival between the exposed and non-exposed groups and the safety of the "TCM formula". RESULTS: There were 6 cases of shedding during the experiment and the shedding rate was 3.9 %. The 2-year rate of invasive disease-free survival in the exposed team was 88.7 % and the non-exposed group was 82.5 %. Logistic multivariate regression analysis predicted that "TCM formula" could reduce the disease-related recurrence and metastasis rate by 11 % (OR = 0.89, 95 % CI 0.37-0.956, P<0.05). Through K-M survival analysis, TNBC patients with age ≤35 years and regional lymph node stage N1 may be the benefit group of "TCM formula"(P<0.05). During the study, the incidence of total adverse events was 8.2 % in the exposed group, mainly manifested as stomach discomfort, diarrhea, and hepatocyte damage. CONCLUSION: 1. In the exposed group, the two-year rate of invasive disease-free survival increased by 6.2 % compared with the non-exposed group(P>0.05). 2. According to K-M survival analysis, TNBC patients with age ≤35 years and regional lymph node metastasis to N1 may be potential beneficiaries of "TCM formula". 3. "TCM Formula" is safe and tolerable to most patients.


Assuntos
Medicina Tradicional Chinesa/métodos , Metástase Neoplásica/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/mortalidade , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/mortalidade , Adulto , Idoso , Estudos de Coortes , Intervalo Livre de Doença , Feminino , Humanos , Pessoa de Meia-Idade , Estudos Prospectivos , Análise de Sobrevida
15.
Ann Transl Med ; 8(13): 818, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32793663

RESUMO

BACKGROUND: Cumulative evidence indicates that LOXL1 and VEGF-a play important roles in extracellular matrix formation and angiogenesis, respectively. The disorder of extracellular matrix and angiogenesis are the key factors of pathogenesis of age-related macular degeneration (AMD). We hypothesized that rs1048661 (T>G) in the LOXL1 gene and rs3025039 (C>T) in the VEGFA gene might be associated with risk of AMD. METHODS: A total of 533 unrelated Chinese subjects, 286 cases (247 with early AMD and 39 with late neovascular AMD) and 247 controls, were included in the study. The gene sequences of LOXL1 rs1048661 and VEGFA rs3025039 were amplified by polymerase chain reaction and genotyped. Interaction between rs1048661 and rs3025039 on AMD risk was also assessed. RESULTS: LOXL1 rs1048661 but not VEGFA rs3025039 was associated with a significantly increased risk of AMD. The adjusted odds ratio was 1.6 (95% CI, 1.1-2.5) for rs1048661 TT + GT genotype compared with GG homozygotes in the dominant model analysis. Moreover, there was a significant gene-gene interaction between these two polymorphic loci. In VEGFA rs3025039 CC + CT genotype which indicated sufficient expression of VEGF-a, LOXL1 rs1048661 had odds ratios of 1.7 (95% CI, 1.1-2.7) for early AMD and 3.6 (95% CI, 1.1-12.3) for late neovascular AMD in the dominant model analysis. However, LOXL1 rs1048661 did not confer the risk of AMD in subjects harboring VEGFA rs3025039 TT genotype which indicated decreased expression of VEGF-a. CONCLUSIONS: Our findings suggest that LOXL1 rs1048661 (T>G) may be involved in the risk of AMD. In addition, LOXL1 rs1048661 and VEGFA rs3025039 interacted to confer the development of AMD, especially for late-stage neovascular AMD. Our data need to be further validated.

16.
JAMA Oncol ; 6(9): 1390-1396, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32789480

RESUMO

Importance: The value of platinum-based adjuvant chemotherapy in patients with triple-negative breast cancer (TNBC) remains controversial, as does whether BRCA1 and BRCA2 (BRCA1/2) germline variants are associated with platinum treatment sensitivity. Objective: To compare 6 cycles of paclitaxel plus carboplatin (PCb) with a standard-dose regimen of 3 cycles of cyclophosphamide, epirubicin, and fluorouracil followed by 3 cycles of docetaxel (CEF-T). Design, Setting, and Participants: This phase 3 randomized clinical trial was conducted at 9 cancer centers and hospitals in China. Between July 1, 2011, and April 30, 2016, women aged 18 to 70 years with operable TNBC after definitive surgery (having pathologically confirmed regional node-positive disease or node-negative disease with tumor diameter >10 mm) were screened and enrolled. Exclusion criteria included having metastatic or locally advanced disease, having non-TNBC, or receiving preoperative anticancer therapy. Data were analyzed from December 1, 2019, to January 31, 2020, from the intent-to-treat population as prespecified in the protocol. Interventions: Participants were randomized to receive PCb (paclitaxel 80 mg/m2 and carboplatin [area under the curve = 2] on days 1, 8, and 15 every 28 days for 6 cycles) or CEF-T (cyclophosphamide 500 mg/m2, epirubicin 100 mg/m2, and fluorouracil 500 mg/m2 every 3 weeks for 3 cycles followed by docetaxel 100 mg/m2 every 3 weeks for 3 cycles). Main Outcomes and Measures: The primary end point was disease-free survival (DFS). Secondary end points included overall survival, distant DFS, relapse-free survival, DFS in patients with germline variants in BRCA1/2 or homologous recombination repair (HRR)-related genes, and toxicity. Results: A total of 647 patients (mean [SD] age, 51 [44-57] years) with operable TNBC were randomized to receive CEF-T (n = 322) or PCb (n = 325). At a median follow-up of 62 months, DFS time was longer in those assigned to PCb compared with CEF-T (5-year DFS, 86.5% vs 80.3%, hazard ratio [HR] = 0.65; 95% CI, 0.44-0.96; P = .03). Similar outcomes were observed for distant DFS and relapse-free survival. There was no statistically significant difference in overall survival between the groups (HR = 0.71; 95% CI, 0.42-1.22, P = .22). In the exploratory and hypothesis-generating subgroup analyses of PCb vs CEF-T, the HR for DFS was 0.44 (95% CI, 0.15-1.31; P = .14) in patients with the BRCA1/2 variant and 0.39 (95% CI, 0.15-0.99; P = .04) in those with the HRR variant. Safety data were consistent with the known safety profiles of relevant drugs. Conclusions and Relevance: These findings suggest that a paclitaxel-plus-carboplatin regimen is an effective alternative adjuvant chemotherapy choice for patients with operable TNBC. In the era of molecular classification, subsets of TNBC sensitive to PCb should be further investigated. Trial Registration: ClinicalTrials.gov Identifier: NCT01216111.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carboplatina/administração & dosagem , Paclitaxel/administração & dosagem , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Proteína BRCA1/genética , Proteína BRCA2/genética , Carboplatina/efeitos adversos , Quimioterapia Adjuvante/efeitos adversos , Intervalo Livre de Doença , Feminino , Mutação em Linhagem Germinativa/genética , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Paclitaxel/efeitos adversos , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia
17.
Quant Imaging Med Surg ; 10(2): 451-463, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32190570

RESUMO

BACKGROUND: To study the predictive value of semi-quantitative pleural effusion and pulmonary consolidation for acute pancreatitis (AP) severity. METHODS: Thorax-abdominal computed tomography (CT) examinations were performed on 309 consecutive AP patients in a single center. Among them, 196 were male, and 113 were female, and the average age was 50±16 years. The etiology of AP was biliary in 43.7% (n=135), hyperlipidemia in 22.0% (n=68), alcoholic in 7.4% (n=23), trauma in 0.6% (n=2), and postoperative status in 1.6% (n=5) cases; 24.6% (n=76) of patients did not have specified etiologies. The prevalence of pleural effusion and pulmonary consolidation was noted. The pleural effusion volume was quantitatively derived from a CT volume evaluation software tool. The pulmonary consolidation score was based on the number of lobes involved in AP. Each patient's CT severity index (CTSI), acute physiology and chronic health evaluation II (APACHE II) scoring system, and bedside index for severity in acute pancreatitis (BISAP) scores were obtained. The semi-quantitative pleural effusion and pulmonary consolidation were compared to these scores and clinical outcomes by receiver operator characteristic (ROC) curve and area under the curve (AUC) analysis. RESULTS: In the 309 patients, 39.8% had pleural effusion, and 47.9% had pulmonary consolidation. The mean pleural effusion volume was 41.7±38.0 mL. The mean pulmonary consolidation score was 1.0±1.2 points. The mean CTSI was 3.7±1.8 points, the mean APACHE II score was 5.8±5.1 points, and the mean BISAP score was 1.3±1.0 points; 5.5% of patients developed severe AP, and 13.9% of patients developed organ failure. Pleural effusion volume and pulmonary consolidation scores correlated to the scores for the severity of AP. In predicting severe AP, the accuracy (AUC 0.839) of pleural effusion volume was similar to that of the CTSI score (P=0.961), APACHE II score (P=0.757), and BISAP score (P=0.906). The accuracy (AUC 0.805) of the pulmonary consolidation score was also similar to that of the CTSI score (P=0.503), APACHE II score (P=0.343), and BISAP score (P=0.669). In predicting organ failure, the accuracy (AUC 0.783) of pleural effusion volume was similar to that of the CTSI score (P=0.473), APACHE II score (P=0.119), and BISAP score (P=0.980), and the accuracy (AUC 0.808) of the pulmonary consolidation score was also similar to that of the CTSI score (P=0.236), APACHE II score (P=0.293), and BISAP score (P=0.612). CONCLUSIONS: Pleural effusion and pulmonary consolidation are common in AP and correlated to the severity of AP. Furthermore, the pleural effusion volume and pulmonary consolidation lobes can provide early prediction of severe AP and organ failure.

18.
Transl Cancer Res ; 9(1): 155-165, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-35117169

RESUMO

BACKGROUND: To investigate ipsilateral breast tumor recurrence (IBTR) in patients who have undergone breast-conserving surgery (BCS) after neoadjuvant systematic therapy (NST). METHOD: Three hundred and twenty-one patients undergoing BCS after NST and 2,534 patients undergoing initial BCS from June 2008 to June 2017 at Fudan University Shanghai Cancer Center were retrospectively enrolled, and statistical analyses, including propensity score matching, were applied to compare IBTR-free survival. The main factors related to IBTR in the NST group were estimated utilizing univariate and multivariate analyses. RESULTS: After propensity score matching, the 3-year IBTR-free survival rates were 93.7% (95% CI, 90.6-96.8%) in the NST group and 96.9% (95% CI, 94.9-98.9%) in the matched initial BCS group at a median follow-up period of 58 months. IBTR-free survival did not differ statistically between the two groups (P=0.154). According to multivariate analysis in the NST group, tumor-infiltrating lymphocytes (TILs), epidermal growth factor receptor 2 (HER2) status and pathologic ductal carcinoma in situ (DCIS) constituent were the factors related to IBTR after BCS. CONCLUSIONS: BCS after NST and initial BCS have equivalent IBTR-free survival. BCS after NST is a safe and effective therapy in terms of IBTR.

19.
Oncoimmunology ; 8(12): e1673126, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31741776

RESUMO

Toll-like receptor 3 (TLR3) is a viral sensor that induces apoptosis in response to double-stranded RNA (dsRNA). Common genetic changes in the TLR3 gene may influence breast cancer susceptibility and development. However, all of the polymorphisms in the previous study were only markers of the TLR3 gene, not causative polymorphisms. In this study, we performed a case-control study focusing on the relationship between rs5743305 (-926T>A), a single nucleotide polymorphism (SNP) in the promoter region of TLR3, and breast cancer. We found that the genetic variant rs5743305 increased the risk of breast cancer under the dominant and codominant models (dominant model: AT+AA vs TT.: OR = 1.3023, 95%CI: 1.0778-1.5736, P = .0062; codominant model: AA vs. TT: OR = 1.3919, 95%CI: 1.0177-1.9036, P = .0384; AT vs. TT: OR = 1.2799, 95%CI: 1.0475-1.5639, P = .0158) but not under the recessive model (TT vs. AT+AA, OR = 1.2387, 95%CI: 0.9197-1.6682, P = .1588). The same trends were found in the age-adjusted logistic regression study and stage 2 study. Furthermore, the electrophoretic mobility shift assay (EMSA) and luciferase reporter assay showed that rs5743305 decreased the transcriptional activity of TLR3. There was consistently reduced TLR3 mRNA and protein expression in human breast cancer samples from patients with TLR3 - 926A. Therefore, TLR3 rs5743305 increases the risk of breast cancer by decreasing the transcriptional activity of TLR3. This study may provide a better understanding of the genetic architecture underlying disease susceptibility and may advance the potential for preclinical prediction in future genetic testing.

20.
Mol Med Rep ; 20(5): 4045-4258, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31485630

RESUMO

Transgelin 2 (TAGLN2) is a cytoskeletal protein of the calponin family. Abnormal expression of TAGLN2 was observed in various types of cancer. Our previous study reported that TAGLN2 expression was reduced in lymph node­positive breast cancer patients; however, the role of TAGLN2 in breast cancer metastasis remains unknown. In the present study, the role of TAGLN2 in breast cancer metastasis was investigated in vitro and in vivo via Transwell migration, luciferase and flow cytometry assays, and a mouse xenograft model. Proteins interacting with TAGLN2 were identified via co­immunoprecipitation assays and liquid chromatography/mass spectrometry, and the signaling pathway associated with the effects of TAGLN2 was investigated. Additionally, western blotting and reverse transcription­quantitative polymerase chain reaction were performed to further explore the potential pathway in which TAGLN2 may be involved and the mechanism underlying its effects in breast cancer metastasis. The present study reported that TAGLN2 expression was increased by 11.4­fold in patients without distant metastasis compared with those positive for distant metastasis. Knockdown of TAGLN2 resulted in increased cell migration in vitro and promoted lung metastasis in vivo. Additionally, overexpression of TAGLN2 suppressed lung metastasis in a mouse model. Peroxiredoxin 1 (PRDX1), an important reactive oxygen species (ROS) regulator, was revealed to interact with TAGLN2. In addition, mitochondrial redistribution and PRDX1 downregulation were reported following TAGLN2 silencing, which promoted ROS production and nuclear factor (NF)­κB activation in breast cancer cells. This induced the expression of metastasis­associated genes, including C­X­C chemokine receptor 4, matrix metalloproteinase (MMP)1 and MMP2. The present study proposed TAGLN2 to function as a tumor suppressor and that loss of TAGLN2 may promote the metastasis of breast cancer by activating the ROS/NF­κB signaling pathway.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Regulação Neoplásica da Expressão Gênica , Proteínas dos Microfilamentos/genética , Proteínas Musculares/genética , NF-kappa B/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Adulto , Idoso , Animais , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Cromatografia Líquida , Modelos Animais de Doenças , Feminino , Humanos , Camundongos , Pessoa de Meia-Idade , Modelos Biológicos , Estadiamento de Neoplasias , Fenótipo , Espectrometria de Massas em Tandem , Microambiente Tumoral/genética
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...