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1.
Food Chem ; 338: 127799, 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-32798816

RESUMO

An emerging blanching technology, namely vacuum-steam pulsed blanching (VSPB) was employed to blanch the carrots and its effects on blanching efficiency, microstructure and ultrastructure, drying kinetics, colour, texture, phytochemicals (phenolics and ß-carotene) and antioxidant capacity of carrot slices were explored and compared with the traditional hot water blanching. Results showed that both blanching treatments enhanced the drying velocity and shortened the drying time by 25.9% compared with untreated samples. VSPB yielded higher blanching efficiency, better colour (more red and yellow), greater antioxidant capacity and higher preservation of phytochemicals compared with hot water blanched samples. Especially, compared to hot water blanched carrots, the p-hydroxybenzoic acid, ferulic acid, and caffeic acid content of VSPB samples increased of 106.6%, 42.0%, and 19.0%, respectively. Interestingly, the chlorogenic acid content in the blanched carrot increased more than 220 times compared to fresh samples. Ultrastructure and microstructure observation clarify the mechanism of quality enhancement of VSPB.

2.
Yi Chuan ; 42(10): 965-978, 2020 Oct 20.
Artigo em Chinês | MEDLINE | ID: mdl-33229322

RESUMO

Elevated serum level of low density lipoprotein cholesterol (LDL-C) is the leading risk factor for cardiovascular disease. LDL receptor (LDLR)-mediated LDL clearance is the major factor determining the LDL-C level in the circulation. LDL binds to the LDLR on the cell surface and enters the cells through classical clathrin-coated vesicles. In the acidic endosome, LDLR is uncoupled from LDL and recycles back to the cell surface. The released LDL is transported to the lysosome for degradation. The proprotein convertase subtilisin kexin type 9 (PCSK9) gene encodes a hepatic secretory protein, and its mutations are strongly associated with levels of LDL-C. We and others have shown that PCSK9 directly interacts with LDLR on the cell surface and both are internalized through the clathrin-coated vesicles. However, in the acidic endosome, PCSK9 and LDLR form a tight complex and are targeted to lysosome for degradation, thereby reducing the level of LDLR on the surface of hepatocytes and decreasing hepatic clearance of LDL-C, which plays an important role in maintaining a relatively constant level of LDL in the plasma. Thus, blocking PCSK9 function has become a new strategy to treat hypercholesterolemia.In this review, we will summarize the latest progress in the functional and mechanistic studies of PCSK9 and also highlight the research progress of PCSK9 inhibitors. It aims to provide a reference for the study of PCSK9-LDLR pathway and the regulation of cholesterol metabolism.

3.
Breastfeed Med ; 2020 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-33156688

RESUMO

Background: This study aimed to explore the effect of breast milk and sodium bicarbonate solution used in oral care of infants with tracheal intubation after cardiothoracic surgery. Methods: A randomized clinical controlled trial was conducted in a provincial hospital in China. Fifty infantile patients were randomly divided into two groups: the patients in the study group (n = 25) used breast milk for oral care and the patients in the control group (n = 25) used sodium bicarbonate solution for oral care. The relevant clinical data were recorded, including the mechanical ventilation duration, length of intensive care unit (ICU) stay, length of hospital stay, and complications. Results: The length of ICU stay, length of hospital stay, and duration of mechanical ventilation were shorter in the study group, but the difference was not statistically significant (p > 0.05). However, the incidence of thrush and ventilator-associated pulmonary infection in the study group was significantly lower than that in the control group (p < 0.05). Conclusion: The use of breast milk for oral care has a positive effect on the prevention of thrush and ventilator-associated pulmonary infection in infants with tracheal intubation after cardiothoracic surgery.

4.
Biochim Biophys Acta Rev Cancer ; 1874(2): 188444, 2020 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-33031899

RESUMO

Pancreatic cancer is highly lethal, and the most effective treatment is curative resection followed by chemotherapy. Unfortunately, chemoresistance is an extremely common occurrence, and novel treatment modalities, such as immunotherapy and molecular targeted therapy, have shown limited success in clinical practice. Pancreatic cancer is characterized by an abundant stromal compartment. Cancer-associated fibroblasts (CAFs) and the extracellular matrix they deposit account for a large portion of the pancreatic tumor stroma. CAFs interact directly and indirectly with pancreatic cancer cells and can compromise the effects of, and even promote tumorigenic responses to, various treatment approaches. To eliminate these adverse effects, CAFs depletion strategies were developed. Instead of the anticipated antitumor effects of CAFs depletion, more aggressive tumor phenotypes were occasionally observed. The failure of universal stromal depletion led to the investigation of CAFs heterogeneity that forms the foundation for stromal remodeling and normalization. This review analyzes the role of CAFs in therapeutic resistance of pancreatic cancer and discusses potential CAFs-targeting strategies basing on the diverse biological functions of CAFs, thus to improve the outcome of pancreatic cancer treatment.

5.
Int J Phytoremediation ; : 1-8, 2020 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-33126813

RESUMO

Agricultural soil contaminated with potentially toxic metals poses great health risk to humans and it requires long-term remediation. Here, we investigate the remediation of metal-polluted agricultural soil by combining chemical washing with repeated phytoextraction. The polluted field was initially washed with 40 mmol L-1 FeCl3 (F) or 20 mmol L-1 FeCl3 + 40 mmol L-1 citric acid (F + C). After the application of organic fertilizer (O), lime (L), and sepiolite (S), Sedum plumbizincicola was cultivated for three successive crops from 2017 to 2019. Results showed that the soil washed with FeCl3 had high removal efficiencies of Cd (35.2%), Pb (24.3%), and Zn (26.6%). Although the shoot biomass and metal concentrations of S. plumbizincicola decreased significantly in the first crop, there were no significant differences in the subsequent two crops. Throughout the remediation process, the higher total removal efficiencies of Cd, Pb, and Zn were conducted in F + OLS treatment which observed in 71.0, 34.0, and 47.7%, respectively. The results, therefore, conclusively indicated that combining chemical washing with repeated phytoextraction showed considerable potential for the remediation of agricultural soils polluted with multiple metals. However, further studies are required to focus on the amelioration of the degraded soil quality and safe agricultural production.

6.
J Immunother Cancer ; 8(2)2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33055204

RESUMO

BACKGROUND: Tertiary lymphoid structures (TLS) are associated with favorable survival and play a critical role in most solid tumors. However, investigations of TLS are lacking in patients with grade 1 or grade 2 (G1/G2) non-functional pancreatic neuroendocrine tumors (NF-PanNETs). This study aimed to investigate the presence, cellular composition, association with tumor-infiltrating immune cells, and prognostic value of TLS in G1/G2 NF-PanNETs. METHODS: Tumor tissues from a 182-patient Fudan cohort and a 125-patient external validation set were assessed by H&E staining, immunohistochemistry, and/or multispectral fluorescent immunohistochemistry. RESULTS: TLS were identified in more than one-third of patients with G1/G2 NF-PanNETs and were located peritumorally, either just outside the tumor tissue or in the stromal area. TLS were mainly composed of B-cell follicles with germinal centers and T-cell zones with dendritic cells. Kaplan-Meier analyses showed that the presence of TLS correlated with both longer recurrence-free survival (RFS, p<0.001) and overall survival (OS, p=0.001), but the number of TLS had no prognostic significance. Multivariate Cox-regression analyses demonstrated that the presence of TLS, WHO classification, and 8th edition American Joint Committee on Cancer (AJCC8th) tumor-node-metastasis (TNM) stage were independent prognostic factors for RFS (p=0.004, p=0.001, and p<0.001, respectively) and OS (p=0.009, p=0.008, and p=0.019, respectively). These results were confirmed using an external validation set. Finally, a nomogram incorporating the presence of TLS was constructed to predict the probability of 5-year RFS of resected G1/G2 NF-PanNETs, which improved on the current WHO classification and AJCC8th TNM stage. CONCLUSIONS: The presence of TLS is an independent and favorable predictor of resected G1/G2 NF-PanNETs, which may play a role in cancer immunobiology.

7.
Int J Biol Macromol ; 165(Pt A): 1303-1311, 2020 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-33022346

RESUMO

Conidial hydrophobins in fungal pathogens of plants, insects, and humans are required for fungal attachment and are associated with high virulence. They are believed to contribute to the pathogenesis of infection by preventing immune recognition. Here, we refute this generalisation offering a more nuanced analysis. We show that MacHYD3, a hydrophobin located on the conidial surface of the specialist entomopathogenic fungus Metarhizium acridum (narrow host range, kills only locusts and grasshoppers), activates specifically the humoral and cellular immunity of its own host insect, Locusta migratoria manilensis (Meyen) but not that of other non-host insects. When topically applied to the cuticle, purified MacHYD3 improved the resistance of locusts to both specialist and generalist fungal pathogens (wide host range) but had no effect on the fungal resistance of other insects, including Spodoptera frugiperda and Galleria mellonella. Hydrophobins extracted from the generalist fungal pathogens M. anisopliae and Beauveria bassiana had no effect on the resistance of locusts to fungal infection. Thus, the host locust has evolved to recognize the conidial hydrophobin of its specialist fungal pathogen, whereas conidial hydrophobins from generalist fungi are able to evade recognition. Our results distinguish the immunogenic potential of conidial hydrophobins between specialist and generalist fungi.

9.
J Cardiothorac Surg ; 15(1): 309, 2020 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-33036645

RESUMO

OBJECTIVE: To investigate the effect of early oral stimulation with breast milk on the feeding behavior of infants after congenital cardiac surgery. METHODS: Infants with congenital heart disease were randomly divided into the breast milk oral stimulation group (n = 23), physiological saline oral stimulation group (n = 23) and control group (n = 23). Debra Beckman's oral exercise program was used with breast milk and physiological saline in the breast milk oral stimulation group and the physiological saline oral stimulation group, respectively. The time oral feeding and total oral nutrition were started, the length of intensive care unit (ICU) stay and hospital stay, weight and the complications at discharge were recorded for each group and statistically analyzed. RESULTS: The time oral feeding and total oral nutrition were started and the length of ICU stay and hospital stay were significantly less in the breast milk oral stimulation group and physiological saline oral stimulation group than in the control group (P < 0.05). There were no significant differences in other indicators between the breast milk oral stimulation group and the physiological saline oral stimulation group, except for the time total oral nutrition began (P < 0.05). However, there were no significant differences in weight or complications at discharge among the three groups (P > 0.05). CONCLUSION: Early oral stimulation exercises with breast milk can help infant patients quickly recover total oral nutrition and reduce the length of ICU and hospital stay after cardiac surgery.

10.
World J Surg ; 2020 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-32901325

RESUMO

BACKGROUND: There lacks an ideal model for accurately predicting clinically relevant postoperative pancreatic fistula (CR-POPF) after pancreatoduodenectomy (PD). This study aimed at developing a nomogram with high accuracy in predicting CR-POPF after PD. METHODS: A total of 1182 patients undergoing PD in the First Affiliated Hospital of Sun Yat-sen University (FAHSYSU, n = 762) and Fudan University Shanghai Cancer Center (FUSCC, n = 420) between January 2010 and May 2018 were enrolled. The patients from FAHSYSU were assigned as testing cohort, and those from FUSCC were used as external validation cohort. Univariate and multivariate logistic regression analyses were performed to determine the predictive factors for CR-POPF. Nomogram was developed on the basis of significant predictors. The performance of nomogram was evaluated by area under receiver operating characteristic (ROC) curve (AUC), calibration curve, and decision curve analysis. RESULTS: In testing cohort, 87 out of 762 patients developed CR-POPF. Three predictors were significantly associated with CR-POPF, including body mass index ≥24.0 kg/m2, pancreatic duct diameter <3 mm, and drainage fluid amylase on postoperative day 1 ≥2484 units/L (all p ≤ 0.001). Prediction of nomogram was accurate with AUC of 0.934 (95% confidence interval [CI]: 0.914-0.950) in testing cohort and 0.744 (95% CI: 0.699-0.785) in external validation cohort. The predictive accuracy of nomogram was better than that of previously proposed fistula risk scores both in testing and external validation cohort (all p < 0.05). CONCLUSIONS: The novel nomogram based on three easily available parameters could accurately predict CR-POPF after PD. It would have high clinical value due to its accuracy and convenience.

11.
Acta Pharmacol Sin ; 2020 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-32868906

RESUMO

Aberrant activation of signal transducer and activator of transcription 3 (STAT3) plays a critical role in many types of cancers. As a result, STAT3 has been identified as a potential target for cancer therapy. In this study we identified 10,11-dehydrocurvularin (DCV), a natural-product macrolide derived from marine fungus, as a selective STAT3 inhibitor. We showed that DCV (2-8 µM) dose-dependently inhibited the proliferation, migration and invasion of human breast cancer cell lines MDA-MB-231 and MDA-MB-468, and induced cell apoptosis. In the two breast cancer cell lines, DCV selectively inhibited the phosphorylation of STAT3 Tyr-705, but did not affect the upstream components JAK1 and JAK2, as well as dephosphorylation of STAT3. Furthermore, DCV treatment strongly inhibited IFN-γ-induced STAT3 phosphorylation but had no significant effect on IFN-γ-induced STAT1 and STAT5 phosphorylation in the two breast cancer cell lines. We demonstrated that the α, ß-unsaturated carbonyl moiety of DCV was essential for STAT3 inactivation. Cellular thermal shift assay (CETSA) further revealed the direct engagement of DCV with STAT3. In nude mice bearing breast cancer cell line MDA-MB-231 xenografts, treatment with DCV (30 mg·kg-1·d-1, ip, for 14 days) markedly suppressed the tumor growth via inhibition of STAT3 activation without observed toxicity. Our results demonstrate that DCV acts as a selective STAT3 inhibitor for breast cancer intervention.

12.
Chem Commun (Camb) ; 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32930292

RESUMO

Herein, we have synthesized successfully a three-dimensional/two dimensional (3D/2D) core-shell Cu2O@Fe-Ni3S2 nanoflower on copper foam at room temperature. Remarkably, by virtue of rich active sites and vacancies, large surface area, high conductivity and close contact with the electrolyte, the Cu2O@Fe-Ni3S2 catalyst exhibits superior stability and oxygen evolution reaction performance.

13.
Am J Chin Med ; 48(6): 1369-1383, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32933311

RESUMO

Age-related myocardial dysfunction is a very large healthcare burden. Here, we aimed to investigate whether ginsenoside Rb1 (Rb1) improves age-related myocardial dysfunction and to identify the relevant molecular mechanism. Young mice and aged mice were injected with Rb1 or vehicle for 3 months. Then, their cardiac function was inspected by transthoracic echocardiography. Serum and myocardium tissue were collected from all mice for histological or molecular expression analyses, including aging-related proteins, markers relevant to fibrosis and inflammation, and markers indicating the activation of the nuclear factor-kappa B (NF-[Formula: see text]B) pathway. Compared with the control condition, Rb1 treatment significantly increased the ejection fraction percentage and significantly decreased the internal diameter and volume of the left ventricle at the end-systolic and end-diastolic phases in aged mice. Rb1 treatment reduced collagen deposition and collagen I, collagen III, and transforming growth factor-[Formula: see text]1 protein expression levels in aged hearts. Rb1 also decreased the aging-induced myocardial inflammatory response, as measured by serum or myocardial interleukin-6 and tumor necrosis factor-[Formula: see text] levels. Furthermore, Rb1 treatment in aged mice increased cytoplasmic NF-[Formula: see text]B but decreased nuclear NF-[Formula: see text]B, which indicated the suppression of the NF-[Formula: see text]B signaling pathway by regulating the translocation of NF-[Formula: see text]B. Rb1 could alleviate aging-related myocardial dysfunction by suppressing fibrosis and inflammation, which is potentially associated with regulation of the NF-[Formula: see text]B signaling pathway.


Assuntos
Envelhecimento , Ginsenosídeos/farmacologia , Ginsenosídeos/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , NF-kappa B/genética , NF-kappa B/metabolismo , Fitoterapia , Animais , Anti-Inflamatórios , Colágeno/metabolismo , Feminino , Expressão Gênica/efeitos dos fármacos , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/metabolismo , Camundongos Endogâmicos C57BL , Transdução de Sinais , Volume Sistólico/efeitos dos fármacos
14.
Acta Pharmacol Sin ; 2020 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-32989235

RESUMO

Excessive activation of NLRP3 inflammasome is associated with the pathogenesis of inflammatory diseases. Pristimerin (Pri) is a quinonoid triterpene derived from traditional Chinese medical herb Celastraceae and Hippocrateaceae. Pri has shown antifungal, antibacterial, antioxidant, and anticancer activities. In this study we investigated whether NLRP3 inflammasome was associated with the anti-inflammatory activity of Pri. We showed that Pri (0.1-0.4 µM) dose-dependently blocked caspase-1 activation and IL-1ß maturation in LPS-primed mouse bone-marrow-derived macrophages (BMDMs). Pri specifically inhibited NLRP3 inflammasome activation, had no visible effects on NLRC4 and AIM2 inflammasome activation. Furthermore, we demonstrated that Pri blocked the assembly of the NLRP3 inflammasome via disturbing the interaction between NEK7 and NLRP3; the α, ß-unsaturated carbonyl moiety of Pri was essential for NLRP3 inflammasome inactivation. In LPS-induced systemic inflammation mouse model and MSU-induced mouse peritonitis model, preinjection of Pri (500 µg/kg, ip) produced remarkable therapeutic effects via inhibition of NLRP3 inflammasome in vivo. In HFD-induced diabetic mouse model, administration of Pri (100 µg· kg-1 ·d-1, ip, for 6 weeks) reversed HFD-induced metabolic disorders via suppression of NLRP3 inflammasome activation. Taken together, our results demonstrate that Pri acts as a NLRP3 inhibitor, suggesting that Pri might be useful for the treatment of NLRP3-associated diseases.

16.
Oncogene ; 39(36): 5825-5838, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32753651

RESUMO

Chemoresistance is a major obstacle to prolonging pancreatic ductal adenocarcinoma (PDAC) patient survival. TET1 is identified as the most important epigenetic modification enzyme that facilitates chemoresistance in cancers. However, the chemoresistance mechanism of TET1 in PDAC is unknown. This study aimed to determine the role of TET1 in the chemoresistance of PDAC. TET1-associated chemoresistance in PDAC was investigated in vitro and in vivo. The clinical significance of TET1 was analyzed in 228 PDAC patients by tissue microarray profiling. We identified that TET1 downregulation is caused by its promoter hypermethylation and correlates with poor survival in PDAC patients. In vitro and in vivo functional studies performed by silencing or overexpressing TET1 suggested that TET1 is able to suppress epithelial-mesenchymal transition (EMT) and sensitize PDAC cells to 5FU and gemcitabine. Then RNA-seq, whole genome bisulfite sequencing (WGBS) and ChIP-seq were used to explore the TET1-associated pathway, and showed that TET1 promotes the transcription of CHL1 by binding and demethylating the CHL1 promoter, which consequently inhibits the Hedgehog pathway. Additionally, inhibiting Hedgehog signaling by CHL1 overexpression or the Hedgehog pathway inhibitor, GDC-0449, reversed the chemoresistance induced by TET1 silencing. Regarding clinical significance, we found that high TET1 and high CHL1 expression predicted a better prognosis in resectable PDAC patients. In summary, we demonstrated that TET1 reverses chemoresistance in PDAC by downregulating the CHL1-associated Hedgehog signaling pathway. PDAC patients with a high expression levels of TET1 and CHL1 have a better prognosis.

17.
Front Genet ; 11: 738, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32765588

RESUMO

Background and Aims: Hirschsprung's disease (HSCR) is a rare genetically heterogeneous congenital disorder. A recent study based on whole genome sequencing demonstrated that common variants at four novel loci, which contained two intronic variants on CASQ2 and PLD1, and intergenic variants located between SLC4A7 and EOMES at 3p24.1, and between LINC01518 and LOC283028 at 10q11.21, were associated with HSCR susceptibility. To validate these associations with HSCR susceptibility, we performed a case-control study in a Han Chinese sample set. Methods: We selected four previously identified single nucleotide polymorphisms (SNPs) for replication, along with tag SNPs to cover the four associated regions. In total, 61 SNPs were genotyped in 420 HSCR patients and 1,665 healthy controls from the Han Chinese population. Results: None of the 14 tag SNPs in the CASQ2 gene region, including the previously associated rs9428225, showed an association with HSCR. Among the 24 tag SNPs from the SLC4A7-EOMES region at 3p24.1, rs2642925 [odds ratio (OR) = 1.41, 95% confidence interval (95% CI) = 1.10-1.79; P Additive = 0.007] and the previously associated SNP rs9851320 showed a suggestive association (OR = 1.22, 95% CI = 1.01-1.47; P Additive = 0.042). A non-synonymous SNP, rs2287579, in PLD1 showed a suggestive association with HSCR susceptibility (OR = 1.71, 95% CI = 1.18-2.46; P Additive = 0.004). Additionally, the previously associated PLD1 SNP rs12632766 showed a suggestive significance (OR = 1.20, 95% CI = 1.01-1.42, P Additive = 0.038). In the LINC01518-LOC283028 region at 10q11.21, three SNPs meet the study-wide significance threshold. Rs17153309 was the most associated SNP (OR = 1.60, 95% CI = 1.34-1.90; P Additive = 1.13 × 10-7). The previously associated SNP rs1414027 also showed significant association (OR = 1.43, 95% CI = 1.20-1.70, P Additive = 3.92 × 10-5). Two associated SNPs at 10q11.21 (rs1414027 and rs624804) were expression quantitative trait loci in digestive tract tissues from GTEx databases. Conclusions: Our results confirmed that variants of the LINC01518-LOC283028 region were associated with HSCR in the Han Chinese population. Additionally, the susceptibility of SNPs in the LINC01518-LOC283028 region were associated with the expression levels of nearby genes. These results provide new insight into the pathogenesis of HSCR.

18.
Pest Manag Sci ; 2020 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-32776685

RESUMO

BACKGROUND: The leaf surface microstructure can greatly influence predator feeding behavior. However, its effects on predator oviposition preference, which is crucial for arthropod fitness at the population level, are largely unknown. This study aimed to test leaf discs and plants of five common host plant species of Bemisia tabaci, including Chinese kale, cotton, cucumber, eggplant, and sweetpotato, to determine the oviposition preference and offspring and adult performance of the whitefly predator Serangium japonicum. Cannibalism risk, attachment force, microstructure of the abaxial leaf surface (ALS), and ladybeetle tarsal morphology were examined. RESULTS: Ladybeetle's oviposition preference had no correlation with offspring performance but positively correlated with fecundity. Further, oviposition preference to leaf discs and fecundity positively correlated with attachment force. The cannibalism risk was not significantly different between plant species. The ALS of Chinese kale and eggplant supported the smallest and the largest attachment forces, respectively. The first one had epicuticular wax crystals, whereas the latter had stellate trichomes. The ALS of cotton and sweetpotato did not bear wax crystals or long trichomes. Cucumber leaves were covered with tapered trichomes. Tenant setae on the distal second tarsomere and a pair of curved, tapered claws on the distal fourth tarsomere were the attachment structures of S. japonicum, which interacted with the plant surface structures and generated the attachment force. CONCLUSION: Plant morphological traits, associated with ladybeetle attachment force and adult performance might be key factors in ladybeetle oviposition preference, and are expected to occur in other host plant herbivore-predator systems.

20.
Neuroendocrinology ; 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32668427

RESUMO

OBJECTIVE: The efficacy of the CAPTEM regimen has been demonstrated in metastatic neuroendocrine neoplasms (NENs), but due to varying response rates among the patients, biomarkers to predict its response are greatly needed. Here, we investigated the clinical utility of a Ki-67 index to predict the CAPTEM regimen objective responses and select patients who could benefit from this regimen. METHODS: Metastatic NENs patients treated with the CAPTEM regimen from 4 high-volume medical centers were selected and grouped in a training and validation cohort. The classification and regression tree (CART) was generated to identify the optimal threshold of Ki-67 for stratifying the patients into different Ki-67 range groups based on their response to the CAPTEM regimen. Results and Conclusions The overall response rate (ORR) and disease control rate (DCR) of the entire cohort (N = 151) were 26.5% and 76.2%, respectively, with a median progression-free survival (PFS) of 12.0 months. CART analysis showed that patients with the Ki-67 range group 10-40% demonstrated a significantly higher ORR than those with Ki-67 > 40% and < 10% groups (P < 0.001 in the training cohort and P = 0.036 in the validation cohort). Response to the CAPTEM regimen was not influenced by the expression of MGMT or primary tumor location. Multivariate analysis identified the Ki-67 index as the only independent prognostic factor for overall survival (P = 0.031) and PFS (P = 0.006). The proposed Ki-67 index was externally validated and could be used to clinically identify suitable metastatic NENs patients who could achieve an optimal cytoreduction using the CAPTEM regimen.

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