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1.
Genomics ; 2021 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-34666190

RESUMO

Background New biomarkers are needed to identify different clinical outcomes for HER2+ breast cancer (BC). Methods Differential genes of HER2+ BC were screened based on TCGA database. We used WGCNA to identify the genes related to the survival. Genetic Algorithm was used to structure risk prediction model. The prognostic model was validated in GSE data. Results We constructed a risk prediction model of 6 genes to identify prognosis of HER2+ BC, including CLEC9A, PLD4, PIM1, PTK2B, AKNAD1 and C15orf27. Kaplan-Meier curve showed that the model effectively distinguished the survival of HER2+ BC patients. The multivariate Cox regression suggested that the risk model was an independent predictor for HER2+ BC. Analysis related to immune showed that significant differences in immune infiltration between high- and low-risk groups classified by the prognostic model. Conclusions Our study identified a risk prediction model of 6 genes that could distinguish the prognosis of HER2+ BC.

2.
Cancer Med ; 10(19): 6744-6761, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34472719

RESUMO

BACKGROUND: Anthracycline-based chemotherapy (ABC) is one of the standard therapies against breast cancer. However, few guidelines are currently available to optimize the use of ABC. Therefore, the present analysis aimed at determining the profile and treatment patterns of ABC and the association of clinicopathological characteristics with ABC selection. METHODS: We retrospectively analyzed the data of a nation-wide multicenter epidemiological study, which collected the medical records of breast cancer patients receiving chemotherapy in different settings from seven geographic regions in China (NCT03047889). RESULTS: In total, 3393 patients were included, with 2917 treated with ABC. Among them, 553 (89.8%), 2165 (81.7%), and 814 (25.7%) were subjected to ABC as neoadjuvant, adjuvant, and advanced chemotherapy, respectively. The most frequently used regimens were anthracycline-taxane-based combinations for neo- and adjuvant chemotherapy, along with taxanes and oral fluorouracils for the palliative stages. In the overall cohort, patients aged < 40 or 40-65 (p < 0.001), in premenopause (p < 0.001), without comorbidities (p = 0.016), with invasive ductal carcinoma (p= 0.001), high lymph node involvement (p < 0.001), in the pTNM stage II, III, or IV versus stage I (p < 0.001), subjected to mastectomy (p < 0.001) or subjected to sentinel lymph node biopsy combined with axillary lymph node dissection (p = 0.044), or with a decreased disease-free survival (p < 0.001) were more likely to be recommended to ABC. CONCLUSION: Taken together, ABC remained the mainstay of breast cancer treatment, especially in neo and adjuvant therapy. ABC was mainly used as a combination therapy, and the correlation between influencing factors and ABC choice varied during different settings, indicating the preference and different perspectives of medication considered by medical oncologists regarding the use ABC in China.

3.
Ann Med ; 53(1): 1358-1369, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34396843

RESUMO

BACKGROUND: Triple-negative breast cancer (TNBC) represents about 19% of all breast cancer cases in the Chinese population. Lack of targeted therapy contributes to the poorer outcomes compared with other breast cancer subtypes. Comprehensive genomic profiling helps to explore the clinically relevant genomic alterations (CRGAs) and potential therapeutic targets in very-early-relapsed TNBC patients. METHODS: Formalin-fixed paraffin-embedded (FFPE) tumour tissue specimens from 23 patients with very-early-relapsed TNBC and 13 patients with disease-free survival (DFS) more than 36 months were tested by FoundationOne CDx (F1CDx) in 324 genes and select gene rearrangements, along with genomic signatures including microsatellite instability (MSI) and tumour mutational burden (TMB). RESULTS: In total, 137 CRGAs were detected in the 23 very-early-relapsed TNBC patients, averaging six alterations per sample. The mean TMB was 4 Muts/Mb, which was higher than that in non-recurrence patients, and is statistically significant. The top-ranked altered genes were TP53 (83%), PTEN (35%), RB1 (30%), PIK3CA (26%) and BRCA1 (22%). RB1 mutation carriers had shorter DFS. Notably, 100% of these patients had at least one CRGA, and 87% of patients had at least one actionable alteration. In pathway analysis, patients who carried a mutation in the cell cycle pathway were more likely to experience very early recurrence. Strikingly, we detected one patient with ERBB2 amplification and one patient with ERBB2 exon20 insertion, both of which were missed by immunohistochemistry (IHC). We also detected novel alterations of ROS1-EPHA7 fusion for the first time, which has not been reported in breast cancer before. CONCLUSIONS: The comprehensive genomic profiling can identify novel treatment targets and address the limited options in TNBC patients. Therefore, incorporating F1CDx into TNBC may shed light on novel therapeutic opportunities for these very-early-relapsed TNBC patients.

4.
Drug Des Devel Ther ; 15: 3463-3473, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34408400

RESUMO

Background: There are no clinically available prognostic models for patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer treated with everolimus. We aimed to develop a tool to predict the progression-free survival (PFS) and overall survival (OS) of these patients and to identify optimal candidates who would benefit from everolimus-based treatment in this heterogeneous patient population. Methods: The clinical data of patients with HR+, HER2- metastatic breast cancer receiving everolimus between May 2012 and January 2018 at Sun Yat-sen University Cancer Center were retrospectively retrieved. Based on potential prognostic factors derived from multivariate Cox analysis, we established predictive nomogram models for PFS and OS and evaluated their predictive values by means of the concordance index (C-index). Calibration curves were used to estimate the consistency between the actual observations and the nomogram-predicted probabilities. Results: A total of 116 patients with HR+, HER2- metastatic breast cancer were enrolled in this study. Three independent prognostic factors, including the line of everolimus in the metastatic setting, everolimus clinical benefit rate and number of liver metastatic lesions, were identified from the multivariate Cox analysis. Prognostic models for individual survival prediction were established and graphically presented as nomograms. The C-index was 0.738 (95% confidence interval [CI]: 0.710-0.767) for the PFS nomogram and 0.752 (95% CI: 0.717-0.788) for the OS nomogram, which showed favourable discrimination. The calibration curves for the probabilities of 6-, 9-, and 12-month PFS and 1-, 2-, and 3-year OS suggested satisfactory consistency between the actual observations and the predicted probabilities. Conclusion: We constructed convenient nomogram models for patients with HR+, HER2- metastatic breast cancer to individually predict their potential benefits from everolimus in the metastatic setting. The models showed good performance in terms of accuracy, discrimination capacity and clinical application value.

5.
Artigo em Inglês | MEDLINE | ID: mdl-34423531

RESUMO

Zinc biology, featuring intertwining signaling networks and critical importance to human health, witnesses exciting opportunities in the big data era of physiology. Here, we report a class of red- and far-red-emitting Zn2+ probes with Kd values ranging from 190 nM to 74 µM, which are particularly suitable for real-time monitoring the high concentration of Zn2+ co-released with insulin during vesicular secretory events. Compared to the prototypical rhodamine-based Zn2+ probes, the new class exploits morpholino auxochromes which eliminates phototoxicity during long-term live recording of isolated islets. A Si-rhodamine-based Zn2+ probe with high turn-on ratio (>100), whose synthesis was enabled by a new route featuring late-stage N-alkylation, allowed simultaneous recording of Ca2+ influx, mitochondrial signal, and insulin secretion in isolated mouse islets. The time-lapse multicolor fluorescence movies and their analysis, enabled by red-shifted Zn2+ and other orthogonal physiological probes, highlight the potential impact of biocompatible fluorophores on the fields of islet endocrinology and system biology.

6.
JAMA Oncol ; : e213428, 2021 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-34436536

RESUMO

Importance: The effectiveness of the mammalian target of rapamycin (mTOR) inhibitor everolimus in premenopausal women with hormone receptor (HR)-positive/ERBB2-negative advanced breast cancer who experienced disease progression while receiving selective estrogen receptor modulators (SERMs) is unknown. Objective: To compare the effectiveness of everolimus plus letrozole vs letrozole alone in premenopausal women with HR-positive/ERBB2-negative advanced breast cancer who experienced disease progression while receiving SERMs. Design, Setting, and Participants: The Everolimus Trial for Advanced Premenopausal Breast Cancer (MIRACLE) was a multicenter, open-label phase 2 randomized clinical trial of everolimus plus letrozole vs letrozole alone as first-line treatment conducted from December 8, 2014, to September 26, 2018. Participants included premenopausal women with HR-positive, ERBB2-negative advanced breast cancer who experienced disease progression while receiving SERMs. Analysis was performed on an intent-to-treat basis from January 5, 2015, to December 30, 2019. Exposures: Patients were randomly assigned in a 1:1 ratio to receive everolimus (10 mg orally once daily) plus letrozole (2.5 mg orally once daily) (n = 101) or letrozole alone (2.5 mg orally once daily) (n = 98). Both groups received goserelin, 3.6 mg, subcutaneously on day 1 of each 28-day cycle. Patients in the letrozole group were permitted to cross over to receive everolimus with letrozole if disease progression occurred. Main Outcomes and Measures: The primary end point was progression-free survival (PFS), defined as the time from randomization to confirmed disease progression or death due to any cause. Results: A total of 199 women (mean [SD] age, 44.3 [6.3] years) were randomized. Patients receiving everolimus plus letrozole achieved a significantly longer median PFS compared with those receiving letrozole alone (19.4 months [95% CI, 16.3-22.0 months] vs 12.9 months [95% CI, 7.6-15.7 months]; hazard ratio, 0.64 [95% CI, 0.46-0.89]; P = .008). A total of 56 of the 98 patients in the letrozole group (57.1%) were crossed over to also receive everolimus. The median PFS after crossover was 5.5 months (95% CI, 3.8-8.2 months). Conclusions and Relevance: In this randomized clinical trial, PFS was significantly longer among premenopausal patients with HR-positive/ERBB2-negative advanced breast cancer who received everolimus plus letrozole than among those who received letrozole alone. The results revealed that everolimus was effective even among patients receiving treatment with the same endocrine agent after disease progression. Trial Registration: ClinicalTrials.gov Identifier: NCT02313051.

7.
Eur J Endocrinol ; 185(4): 565-576, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34374650

RESUMO

Objective: Progressive beta-cell dysfunction is a hallmark of type 2 diabetes (T2D). Increasing evidence indicates that over-stimulating proinsulin synthesis causes proinsulin misfolding and impairs insulin maturation and storage in db/db mice. However, defective insulin maturation in patients with T2D remains unknown. Methods: We examined intra-islet and intra-cellular distributions of proinsulin and insulin and proinsulin to insulin ratio in the islets of patients with T2D. The expression of transcription factor NKX6.1 and dedifferentiation marker ALDH1A3, as well as glucagon, were detected by immunofluorescence. Results: We identified a novel subgroup of beta cells expressing only proinsulin but not insulin. Importantly, significantly increased proinsulin positive and insulin negative (PI+/INS-) cells were evident in T2D, and this increase was strongly correlated with levels of hemoglobin A1C (HbA1c) in T2D and prediabetes. The percentages of beta cells expressing prohormone convertase 1/3 and carboxypeptidase E were not reduced. Indeed, while proinsulin displayed a higher degree of co-localization with the golgi markers GM130/TGN46 in control beta cells, it appeared to be more diffused within the cytoplasm and less co-localized with GM130/TGN46 in PI+/INS- cells. Furthermore, the key functional transcription factor NKX6.1 markedly decreased in the islets of T2D, especially in the cells with PI+/INS-. The decreased NKX6.1+/PI+/INS+ was strongly correlated with levels of HbA1c in T2D. Almost all PI+/INS- cells showed absence of NKX6.1. Moreover, the percentages of PI+/INS- cells expressing ALDH1A3 were elevated along with an increased acquisition of glucagon immunostaining. Conclusion: Our data demonstrate defective insulin maturation in patients with T2D.


Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Proinsulina/metabolismo , Processamento de Proteína Pós-Traducional/fisiologia , Adulto , Aldeído Oxirredutases/metabolismo , Estudos de Casos e Controles , Desdiferenciação Celular/fisiologia , China , Diabetes Mellitus Tipo 2/patologia , Feminino , Glucagon/metabolismo , Proteínas de Homeodomínio/metabolismo , Humanos , Insulina/metabolismo , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , Células Secretoras de Insulina/fisiologia , Masculino , Pessoa de Meia-Idade , Estado Pré-Diabético/metabolismo , Estado Pré-Diabético/patologia
8.
J Exp Clin Cancer Res ; 40(1): 273, 2021 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-34452627

RESUMO

BACKGROUND: Expression of aberrant cyclin G2 is a key factor contributing to cancer biological processes, including glioma. However, the potential underlying mechanisms of cyclin G2 in the glioma tumor immune microenvironment remain unclear. METHODS: Co-immunoprecipitation (co-IP), in situ proximity ligation assay (PLA), and in vitro kinase assay were conducted to reveal the underlying mechanism by which cyclin G2 regulates Y10 phosphorylation of LDHA. Further, the biological roles of cyclin G2 in cell proliferation, migration, invasion capacity, apoptosis, glycolysis, and immunomodulation were assessed through in vitro and in vivo functional experiments. Expressions of cyclin G2 and Foxp3 in glioma specimens was determined by immunohistochemistry. RESULTS: In this study, we found that cyclin G2 impeded the interaction between LDHA and FGFR1, thereby decreasing Y10 phosphorylation of LDHA through FGFR1 catalysis. Cyclin G2 inhibited proliferation, migration, invasion capacity, and glycolysis and promoted apoptosis glioma cells via suppressing Y10 phosphorylation of LDHA. Moreover, we further verified that cyclin G2 reversed the immunosuppressive to antitumor immune microenvironment through inhibiting lactate production by glioma cells. Besides, cyclin G2 potentiated PD-1 blockade and exerted strong antitumor immunity in the glioma-bearing mice model. CONCLUSIONS: Cyclin G2 acts as a potent tumor suppressor in glioma and enhances responses to immunotherapy. Our findings may be helpful in selecting glioma patients for immunotherapy trials in the future.

9.
BMC Cancer ; 21(1): 957, 2021 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-34445994

RESUMO

BACKGROUND: The advanced hepatocellular carcinoma (HCC), such as the recurrent tumor after liver transplantation (LT), is an obstacle of HCC treatment. The aim of this study was to discover the underlying mechanism of HCC progression caused by non-coding RNAs (ncRNAs). METHODS: To this end, we investigated the selected patient cohort of matching primary and recurrent HCC after receiving LT. The recurrent tumors after LT were regarded as clinical models of the advanced HCC. Microarrays were used to profile lncRNA and mRNA expression in HCC recurrent and primary tissue samples. The mRNA profile characteristics were analyzed by bioinformatics. Two cell lines, HepG2 and QGY-7703, were used as HCC cell models. The protein-coding potential, length, and subcellular location of the interested lncRNAs were examined by bioinformatics, Northern blot, fluorescent in situ hybridization (FISH), and quantitative RT-PCR (qRT-PCR) assays. HCC cell proliferation was detected by CCK-8, doubling time and proliferation marker gene quantitation assays. DNA replication during the cell cycle was measured by EdU/PI staining and flow cytometry analyses. Promoter activity was measured using a luciferase reporter assay. Interactions between DNA, RNA, and protein were examined by immunoprecipitation and pull-down assays. The miRNA-target regulation was validated by a fluorescent reporter assay. RESULTS: Both lncRNA and mRNA profiles exhibited characteristic alterations in the recurrent tumor cells compared with the primary HCC. The mRNA profile in the HCC recurrent tissues, which served as model of advanced HCC, showed an aberrant cell cycle regulation. Two lncRNAs, the highly expressed lncRNA in recurrent HCC (HERH)-1 and HERH-4, were upregulated in the advanced HCC cells. HERH-1/4 enhanced proliferation and promoted DNA replication and G1-S transition during the cell cycle in HCC cells. HERH-1 interacted with the transcription factor CREB1. CREB1 enhanced cyclin A2 (CCNA2) transcription, depending on HERH-1-CREB1 interaction. HERH-4 acted as an miR-29b/c sponge to facilitate CCNA2 protein translation through a competing endogenous RNA (ceRNA) pathway. CONCLUSIONS: The oncogenic lncRNA HERH-1/4 promoted CCNA2 expression at the transcriptional and post-transcriptional levels and accelerated cell cycle progression in HCC cells. The HERH-1-CREB1-CCNA2 and HERH-4-miR-29b/c-CCNA2 axes served as molecular stimuli for HCC advance.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/patologia , Ciclo Celular , Ciclina A2/metabolismo , Regulação Neoplásica da Expressão Gênica , Neoplasias Hepáticas/patologia , RNA Longo não Codificante/genética , Apoptose , Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Proliferação de Células , Ciclina A2/genética , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Prognóstico , Taxa de Sobrevida , Células Tumorais Cultivadas
11.
Breast Cancer Res Treat ; 187(3): 759-768, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33860389

RESUMO

PURPOSE: In the KATHERINE study (NCT01772472), patients with HER2-positive early breast cancer (EBC) and residual invasive disease after neoadjuvant chemotherapy plus HER2-targeted therapy who were treated with adjuvant trastuzumab emtansine (T-DM1) had a 50% reduction in the risk of an invasive disease-free survival (IDFS) event compared to patients treated with adjuvant trastuzumab. In metastatic disease, T-DM1 has resulted in higher rates of thrombocytopenia in Asian versus non-Asian patients. Here, we report safety and efficacy in Chinese patients from KATHERINE. METHODS: Patients with HER2-positive EBC and residual invasive disease after taxane- and trastuzumab-containing neoadjuvant chemotherapy followed by surgery were randomized 1:1 to 14 cycles of adjuvant T-DM1 or trastuzumab. The primary endpoint was time to an IDFS event. RESULTS: Among Chinese patients (T-DM1 n = 51, trastuzumab n = 50), T-DM1 treatment resulted in a 43% reduction in risk of an IDFS event compared to trastuzumab (HR = 0.57; 95% CI 0.25-1.31), with similar results for secondary endpoints. As in the global population, Chinese patients receiving T-DM1 versus trastuzumab had more grade ≥ 3 adverse events (AEs; 39.2% versus 4.1%) and AEs leading to treatment discontinuation (27.5% versus 0%). The most common grade ≥ 3 AE with T-DM1 was thrombocytopenia (21.6%), a frequency higher than the frequency in the global population (5.7%). Grade ≥ 3 hemorrhage was reported in 1 patient (T-DM1 arm). CONCLUSIONS: In the KATHERINE study, T-DM1 demonstrated increased efficacy compared to trastuzumab in Chinese patients. Consistent with previous data in Asian patients, T-DM1 was associated with more grade ≥ 3 AEs, and AEs leading to discontinuation, which was driven by an increase in thrombocytopenia.


Assuntos
Neoplasias da Mama , Maitansina , Ado-Trastuzumab Emtansina , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , China , Feminino , Humanos , Maitansina/efeitos adversos , Terapia Neoadjuvante , Receptor ErbB-2/genética , Trastuzumab/efeitos adversos
12.
Cancer Chemother Pharmacol ; 88(1): 131-141, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33835229

RESUMO

PURPOSE: This phase 1, open-label, single-arm clinical trial evaluated pharmacokinetics, safety, and biomarker activity of palbociclib-letrozole as first-line treatment for estrogen receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer (ABC) in postmenopausal Chinese women to support palbociclib approval in China. METHODS: Patients received palbociclib 125 mg once daily (3/1 schedule) plus letrozole 2.5 mg once daily. Blood samples were collected predose and ≤ 120 h after single and multiple doses of palbociclib. The incidence and severity of adverse events were reported. Skin biopsy tissues and blood samples were collected for biomarker assessments. RESULTS: By 31 July 2018, 26 patients were enrolled. After single and multiple dosing, palbociclib maximum plasma concentration was 82.14 and 139.7 ng/mL, apparent clearance was 52.40 and 49.97 L/h, AUCτ was 1217 and 2501 ng∙h/mL, and t½ was 23.46 and 27.26 h, respectively. Levels of Ki67, retinoblastoma protein, and thymidine kinase decreased after palbociclib treatment. A similar safety profile as previously reported was observed. CONCLUSIONS: Pharmacokinetic and pharmacodynamic effects of palbociclib were well characterized in Chinese patients with ABC. Despite higher exposure, pharmacokinetic parameters were similar to those of a previously studied non-Asian population. No palbociclib dose adjustment based on Chinese ethnicity is needed. Palbociclib-letrozole had a manageable safety profile. CLINICAL TRIAL REGISTRATION: NCT02499146.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Letrozol/farmacocinética , Letrozol/uso terapêutico , Piperazinas/farmacocinética , Piperazinas/uso terapêutico , Piridinas/farmacocinética , Piridinas/uso terapêutico , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Grupo com Ancestrais do Continente Asiático , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/metabolismo , Feminino , Humanos , Letrozol/efeitos adversos , Pessoa de Meia-Idade , Piperazinas/efeitos adversos , Pós-Menopausa/metabolismo , Piridinas/efeitos adversos , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Resultado do Tratamento
13.
BioDrugs ; 35(3): 337-350, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33826080

RESUMO

BACKGROUND: HLX02 is an approved biosimilar of trastuzumab. OBJECTIVE: This study aimed to evaluated the efficacy, safety, and immunogenicity of HLX02 compared with reference trastuzumab in patients with human epidermal growth factor receptor 2 (HER2)-positive recurrent or metastatic breast cancer. PATIENTS AND METHODS: This randomized, double-blind, phase III study was conducted at 89 centers in China, the Philippines, Poland, and Ukraine. Eligible patients were randomized (1:1) to receive HLX02 or European Union (EU)-sourced trastuzumab (initial dose of 8 mg/kg, followed by 6 mg/kg every 3 weeks for up to 12 months) in combination with docetaxel intravenously. The primary endpoint was overall response rate up to week 24 (ORR24). Equivalence was declared if the 95% confidence interval (CI) of difference was within ± 13.5%. Safety and immunogenicity were evaluated in patients who received at least one dose of study medication. RESULTS: Between 11 November 2016 and 10 July 2019, a total of 649 patients were enrolled. The ORR24 was 71.3 and 71.4% in the HLX02 (n = 324) and EU-trastuzumab (n = 325) groups, with a difference of - 0.1% (95% CI - 7 to 6.9), which fell entirely in the predefined equivalence margins. No statistically significant differences were observed in all secondary efficacy analyses. Safety profiles and immunogenicity were comparable in HLX02 and EU-trastuzumab groups. In total, 98.8% of patients in each group experienced at least one treatment-emergent adverse event (TEAE), 23.8 and 24.9% experienced serious TEAEs, and 0.6% in each group had antidrug antibodies. CONCLUSIONS: Among patients with HER2-positive recurrent or metastatic breast cancer, HLX02 demonstrated equivalent efficacy and similar safety and immunogenicity to reference trastuzumab. CLINICAL TRIAL REGISTRATION: Chinadrugtrials.org CTR20160526 (12 September 2016), ClinicalTrials.gov NCT03084237 (20 March 2017), EudraCT 2016-000206-10 (27 April 2017).


Assuntos
Neoplasias da Mama , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Docetaxel/uso terapêutico , Humanos , Polônia , Receptor ErbB-2 , Trastuzumab/efeitos adversos
14.
Environ Res ; 197: 111029, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33744267

RESUMO

Sulfur autotrophic denitrification (SAD) process, as an alternative to heterotrophic denitrification (HD) filter, receives growing interest in polishing the effluent from secondary sewage treatment. Although individual studies have indicated several advantages of SAD over HD, rare study has compared these two systems under identical condition and by using real secondary effluent. In this study, two small pilot scale filters (SAD and HD) were designed with identical configuration and operated parallelly by feeding the real secondary effluent from a WWTP. The results showed SAD filter can be started up without the addition of soluble electron donor, although the time (14 days) was about 3 times longer than that of HD filter. The nitrate removal rate of SAD filter at HRT of 1.4 h was measured as 0.268 ± 0.047 kg N/(m3∙d). Similar value was observed in HD filter with supplementing 90 mg/L COD. The COD concentration of effluent always kept lower than that of influent in SAD filter but not in HD filter. In addition, SAD filter could maintain a stable denitrification performance without backwash for 15 days, while decline of nitrate removal rate was observed in HD filter just 2 days after stopping the backwash. This different behavior was further confirmed as the SAD filter had a better hydraulic flow pattern. Analysis according to high-throughput 16S rRNA gene-based Illumina MiSeq sequencing clearly showed the microbial community evolution and differentiation among the samples of seed sludge, SAD and HD filters. Finally, the economic assessment was carried out, showing the operation cost of SAD filter was over 50% lower than that of HD filter.


Assuntos
Desnitrificação , Hidrodinâmica , Reatores Biológicos , Nitratos , Nitrogênio , RNA Ribossômico 16S/genética , Enxofre
15.
BMC Endocr Disord ; 21(1): 47, 2021 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-33711989

RESUMO

BACKGROUND: NKX6.1 is a transcription factor for insulin, as well as a marker for ß cell maturity. Abnormal NKX6.1 expression in ß cells, such as translocation from the nucleus to cytoplasm or lost expression, has been shown as a marker for ß cell dedifferentiation. METHODS: We obtained pancreatic sections from organ donors and immunofluorescence staining with NKX6.1 and insulin was performed to characterize NKX6.1 expression in subjects with or without type 2 diabetes mellitus (T2DM). RESULTS: Our results showed that cells with insulin expression but no nucleic NKX6.1 expression (NKX6.1Nuc-Ins+), and cells with cytoplasmic NKX6.1 expression but no insulin expression (NKX6.1cytIns-) were significantly increased in T2DM subjects and positively correlated with glycated hemoglobin (HbA1c), indicating the elevated ß cell dedifferentiation with NKX6.1 inactivation in T2DM. To investigate whether ß cell dedifferentiation has initiated in subjects with higher risks for T2DM, we next analyzed the association between ß-cell dedifferentiation level in ND subjects with different ages, body mass index, and HbA1c. The results showed the absolute number and percentage of dedifferentiated ß cells with NKX6.1 inactivation did not significantly change in subjects with advanced aging, obesity, or modest hyperglycemia, indicating that the ß cell dedifferentiation might mainly occur after T2DM was diagnosed. CONCLUSION: Our results suggested that NKX6.1 expression in ß cells was changed in type 2 diabetic subjects, evidenced by significantly increased NKX6.1Nuc-Ins+ and NKX6.1cytIns- cells. This abnormality did not occur more frequently in subjects with a higher risk for T2DM, suggesting that ß cell dedifferentiation might be secondary to the pathological changes in T2DM.

16.
Cancer Commun (Lond) ; 41(2): 171-182, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33528890

RESUMO

BACKGROUND: The introductions of anti- human epidermal growth factor receptor-2 (HER2) agents have significantly improved the treatment outcome of patients with HER2-positive breast cancer. BAT8001 is a novel antibody-drug conjugate targeting human epidermal growth factor receptor-2 (HER2)-expressing cells composed of a trastuzumab biosimilar linked to the drug-linker Batansine. This dose-escalation, phase I study was designed to assess the safety, tolerability, pharmacokinetics, and preliminary anti-tumor activity of BAT8001 in patients with HER2-positive locally advanced or metastatic breast cancer. METHODS: This trial was conducted in subjects with histologically confirmed HER2-positive breast cancer (having evaluable lesions and an Eastern Cooperative Oncology Group performance status of 0 or 1) using a 3 + 3 design of escalating BAT8001 doses. Patients received BAT8001 intravenously in a 21-day cycle, with dose escalation in 5 cohorts: 1.2, 2.4, 3.6, 4.8, and 6.0 mg/kg. The primary objective was to evaluate the safety and tolerability of BAT8001. Preliminary activity of BAT8001 was also assessed as a secondary objective. RESULTS: Between March 2017 to May 2018, 29 HER2-positive breast cancer patients were enrolled. The observed dose-limiting toxicities were grade 4 thrombocytopenia and grade 3 elevated transaminase. The maximum tolerated dose was determined to be 3.6 mg/kg. Grade 3 or greater adverse events (AEs) occurred in 14 (48.3%) of 29 patients, including thrombocytopenia in 12 (41.4%) patients, aspartate aminotransferase increased in 4 (13.8%) patients, γ-glutamyl transferase increased in 2 (6.9%) patients, alanine aminotransferase increased in 2 (6.9%) patients, diarrhea in 2 (6.9%) patients. Objective response was observed in 12 (41.4%; 95% confidence interval [CI] = 23.5%-61.1%) and disease control (including patients achieving objective response and stable disease) was observed in 24 (82.8%; 95% CI = 64.2%-94.2%) patients. CONCLUSIONS: BAT8001 demonstrated favorable safety profiles, with promising anti-tumor activity in patients with HER2-positive locally advanced or metastatic breast cancer. BAT8001 has the potential to provide a new therapeutic option in patients with metastatic HER2-positive breast cancer.


Assuntos
Neoplasias da Mama , Imunoconjugados , Anticorpos Monoclonais Humanizados/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Feminino , Humanos , Dose Máxima Tolerável , Trastuzumab/uso terapêutico
17.
Lancet Oncol ; 22(3): 351-360, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33581774

RESUMO

BACKGROUND: Despite therapeutic advances in HER2-positive metastatic breast cancer, resistance to trastuzumab inevitably develops. In the PHOEBE study, we aimed to assess the efficacy and safety of pyrotinib (an irreversible pan-HER inhibitor) plus capecitabine after previous trastuzumab. METHODS: This is an open-label, randomised, controlled, phase 3 trial done at 29 hospitals in China. Patients with pathologically confirmed HER2-positive metastatic breast cancer, aged 18-70 years, who had an Eastern Cooperative Oncology Group performance status of 0 or 1, and had been previously treated with trastuzumab and taxanes were randomly assigned (1:1) to receive oral pyrotinib 400 mg or lapatinib 1250 mg once daily plus oral capecitabine 1000 mg/m2 twice daily on days 1-14 of each 21-day cycle. Randomisation was done via a centralised interactive web-response system with a block size of four or six and stratified by hormone receptor status and previous lines of chemotherapy for metastatic disease. The primary endpoint was progression-free survival according to masked independent central review. Efficacy and safety were assessed in all patients who received at least one dose of the study drugs. Results presented here are from a prespecified interim analysis. This study is registered with ClinicalTrials.gov, NCT03080805. FINDINGS: Between July 31, 2017, and Oct 30, 2018, 267 patients were enrolled and randomly assigned. 134 patients received pyrotinib plus capecitabine and 132 received lapatinib plus capecitabine. At data cutoff of the interim analysis on March 31, 2019, median progression-free survival was significantly longer with pyrotinib plus capecitabine (12·5 months [95% CI 9·7-not reached]) than with lapatinib plus capecitabine (6·8 months [5·4-8·1]; hazard ratio 0·39 [95% CI 0·27-0·56]; one-sided p<0·0001). The most common grade 3 or worse adverse events were diarrhoea (41 [31%] in the pyrotinib group vs 11 [8%] in the lapatinib group) and hand-foot syndrome (22 [16%] vs 20 [15%]). Serious adverse events were reported for 14 (10%) patients in the pyrotinib group and 11 (8%) patients in the lapatinib group. No treatment-related deaths were reported in the pyrotinib group and one sudden death in the lapatinib group was considered treatment related. INTERPRETATION: Pyrotinib plus capecitabine significantly improved progression-free survival compared with that for lapatinib plus capecitabine, with manageable toxicity, and can be considered an alternative treatment option for patients with HER2-positive metastatic breast cancer after trastuzumab and chemotherapy. FUNDING: Jiangsu Hengrui Medicine and National Key R&D Program of China. TRANSLATIONS: For the Chinese translation of the abstract see Supplementary Materials section.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Receptor ErbB-2/metabolismo , Acrilamidas/administração & dosagem , Adulto , Aminoquinolinas/administração & dosagem , Neoplasias da Mama/metabolismo , Neoplasias da Mama/secundário , Capecitabina/administração & dosagem , Feminino , Seguimentos , Humanos , Lapatinib/administração & dosagem , Pessoa de Meia-Idade , Prognóstico , Taxa de Sobrevida
18.
J Clin Invest ; 131(2)2021 01 19.
Artigo em Inglês | MEDLINE | ID: mdl-33463547

RESUMO

Both basal and glucose-stimulated insulin release occur primarily by insulin secretory granule exocytosis from pancreatic ß cells, and both are needed to maintain normoglycemia. Loss of insulin-secreting ß cells, accompanied by abnormal glucose tolerance, may involve simple exhaustion of insulin reserves (which, by immunostaining, appears as a loss of ß cell identity), or ß cell dedifferentiation, or ß cell death. While various sensing and signaling defects can result in diminished insulin secretion, somewhat less attention has been paid to diabetes risk caused by insufficiency in the biosynthetic generation and maintenance of the total insulin granule storage pool. This Review offers an overview of insulin biosynthesis, beginning with the preproinsulin mRNA (translation and translocation into the ER), proinsulin folding and export from the ER, and delivery via the Golgi complex to secretory granules for conversion to insulin and ultimate hormone storage. All of these steps are needed for generation and maintenance of the total insulin granule pool, and defects in any of these steps may, weakly or strongly, perturb glycemic control. The foregoing considerations have obvious potential relevance to the pathogenesis of type 2 diabetes and some forms of monogenic diabetes; conceivably, several of these concepts might also have implications for ß cell failure in type 1 diabetes.


Assuntos
Retículo Endoplasmático/metabolismo , Complexo de Golgi/metabolismo , Secreção de Insulina , Células Secretoras de Insulina/metabolismo , Insulina/biossíntese , Dobramento de Proteína , Precursores de Proteínas/biossíntese , Transdução de Sinais , Animais , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/patologia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Retículo Endoplasmático/patologia , Complexo de Golgi/patologia , Humanos , Células Secretoras de Insulina/patologia , Transporte Proteico
19.
Cell Rep ; 34(1): 108576, 2021 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-33406428

RESUMO

Type 2 diabetes mellitus (T2DM) is recognized as a chronic, low-grade inflammatory disease characterized by insulin resistance and pancreatic ß cell dysfunction; however, the underlying molecular mechanism remains unclear. Here, we report a key ß cell-macrophage crosstalk pathway mediated by the miRNA-29-TNF-receptor-associated factor 3 (TRAF3) axis. ß cell-specific transgenic miR-29a/b/c mice are predisposed to develop glucose intolerance and insulin resistance when fed a high-fat diet (HFD). The metabolic effect of ß cell miR-29 is largely mediated through macrophages because either depletion of macrophages or reconstitution with miR-29-signaling defective bone marrow improves metabolic parameters in the transgenic mice. Mechanistically, our data show that miR-29 promotes the recruitment and activation of circulating monocytes and macrophages and, hence, inflammation, via miR-29 exosomes in a TRAF3-dependent manner. Our results demonstrate the ability of ß cells to modulate the systemic inflammatory tone and glucose homeostasis via miR-29 in response to nutrient overload.

20.
Int J Cancer ; 148(3): 692-701, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-32700765

RESUMO

Although receptor status including estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) of the primary breast tumors was related to the prognosis of breast cancer patients, little information is yet available on whether patient management and survival are impacted by receptor conversion in breast cancer metastases. Using data from the nation-wide multicenter clinical epidemiology study of advanced breast cancer in China (NCT03047889), we report the situation of retesting ER, PR and HER2 status for breast cancer metastases and evaluate the patient management and prognostic value of receptor conversion. In total, 3295 patients were analyzed and 1583 (48.0%) patients retesting receptor status for metastasis. Discordance in one or more receptors between the primary and the metastatic biopsy was found in 37.7% of women. Patients who remained hormone receptor (HR) positive in their metastases had similar progression-free survival of first-line and second-line treatment compared to patients with HR conversion (P > .05). In multivariate analysis, patients who showed ER conversion from negative to positive had longer disease-free survival (DFS) than patients who remained negative in their metastases (hazard ratio, 2.05; 95% confidence interval [CI], 1.45-2.90; P < .001). Patients with PR remained positive and had longer DFS than patients with PR conversion from negative to positive (hazard ratio, 0.56; 95% CI, 0.38-0.83; P = .004). Patients with PR conversion have shorter overall survival than patients with PR remained positive or negative (P = .016 and P = .041, respectively). Our findings showed that the receptors' conversions were common in metastatic breast cancer, and the conversion impacted the survival.


Assuntos
Neoplasias da Mama/mortalidade , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Neoplasias da Mama/metabolismo , Intervalo Livre de Doença , Estudos Epidemiológicos , Feminino , Humanos , Análise Multivariada , Metástase Neoplásica , Prognóstico , Estudos Retrospectivos
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