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1.
Sci Rep ; 11(1): 8002, 2021 Apr 13.
Artículo en Inglés | MEDLINE | ID: mdl-33850196

RESUMEN

The interactions of derivatives of lumisterol (L3) and vitamin D3 (D3) with liver X receptors (LXRs) were investigated. Molecular docking using crystal structures of the ligand binding domains (LBDs) of LXRα and ß revealed high docking scores for L3 and D3 hydroxymetabolites, similar to those of the natural ligands, predicting good binding to the receptor. RNA sequencing of murine dermal fibroblasts stimulated with D3-hydroxyderivatives revealed LXR as the second nuclear receptor pathway for several D3-hydroxyderivatives, including 1,25(OH)2D3. This was validated by their induction of genes downstream of LXR. L3 and D3-derivatives activated an LXR-response element (LXRE)-driven reporter in CHO cells and human keratinocytes, and by enhanced expression of LXR target genes. L3 and D3 derivatives showed high affinity binding to the LBD of the LXRα and ß in LanthaScreen TR-FRET LXRα and ß coactivator assays. The majority of metabolites functioned as LXRα/ß agonists; however, 1,20,25(OH)3D3, 1,25(OH)2D3, 1,20(OH)2D3 and 25(OH)D3 acted as inverse agonists of LXRα, but as agonists of LXRß. Molecular dynamics simulations for the selected compounds, including 1,25(OH)2D3, 1,20(OH)2D3, 25(OH)D3, 20(OH)D3, 20(OH)L3 and 20,22(OH)2L3, showed different but overlapping interactions with LXRs. Identification of D3 and L3 derivatives as ligands for LXRs suggests a new mechanism of action for these compounds.

2.
Eur J Pharm Sci ; 160: 105771, 2021 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-33617948

RESUMEN

AIMS: Cell surface binding immunoglobin protein (csBiP) is predicted to be susceptible to SARS-CoV-2 binding. With a substrate-binding domain (SBD) that binds to polypeptides and a nucleotide-binding domain (NBD) that can initiate extrinsic caspase-dependent apoptosis, csBiP may be a promising therapeutic target for COVID-19. This study aims to identify FDA-approved drugs that can neutralize viral binding and prevent viral replication by targeting the functional domains of csBiP. METHODS: In silico screening of 1999 FDA-approved drugs against the functional domains of BiP were performed using three molecular docking programs to avoid bias from individual docking programs. Top ligands were selected by averaging the ligand rankings from three programs. Interactions between top ligands and functional domains of BiP were analyzed. KEY FINDINGS: The top 10 SBD-binding candidates are velpatasvir, irinotecan, netupitant, lapatinib, doramectin, conivaptan, fenoverine, duvelisib, irbesartan, and pazopanib. The top 10 NBD-binding candidates are nilotinib, eltrombopag, grapiprant, topotecan, acetohexamide, vemurafenib, paritaprevir, pixantrone, azosemide, and piperaquine-phosphate. Among them, Velpatasvir and paritaprevir are antiviral agents that target the protease of hepatitis C virus. Netupitant is an anti-inflammatory drug that inhibits neurokinin-1 receptor, which contributes to acute inflammation. Grapiprant is an anti-inflammatory drug that inhibits the prostaglandin E2 receptor protein subtype 4, which is expressed on immune cells and triggers inflammation. These predicted SBD-binding drugs could disrupt SARS-CoV-2 binding to csBiP, and NBD-binding drugs may falter viral attachment and replication by locking the SBD in closed conformation and triggering apoptosis in infected cells. SIGNIFICANCE: csBiP appears to be a novel therapeutic target against COVID-19 by preventing viral attachment and replication. These identified drugs could be repurposed to treat COVID-19 patients.


Asunto(s)
Antivirales/farmacología , Proteínas de la Membrana/efectos de los fármacos , Acoplamiento Viral/efectos de los fármacos , Antivirales/química , Reposicionamiento de Medicamentos , Inmunoglobulinas/efectos de los fármacos , Modelos Moleculares , Estructura Molecular , Conformación Proteica , Relación Estructura-Actividad , Internalización del Virus
3.
Alzheimers Dement ; 2020 Oct 08.
Artículo en Inglés | MEDLINE | ID: mdl-33090700

RESUMEN

INTRODUCTION: Triggering receptor expressed on myeloid cells-2 (TREM2) is an immune receptor expressed on microglia that also can become soluble (sTREM2). How TREM2 engages different ligands remains poorly understood. METHODS: We used comprehensive biolayer interferometry (BLI) analysis to investigate TREM2 and sTREM2 interactions with apolipoprotein E (apoE) and monomeric amyloid beta (Aß) (mAß42). RESULTS: TREM2 engagement of apoE was protein mediated with little effect of lipidation, showing slight affinity differences between isoforms (E4 > E3 > E2). Another family member, TREML2, did not bind apoE. Disease-linked TREM2 variants within a "basic patch" minimally impact apoE binding. Instead, TREM2 uses a unique hydrophobic surface to bind apoE, which requires the apoE hinge region. TREM2 and sTREM2 directly bind mAß42 and potently inhibit Aß42 polymerization, suggesting a potential role for soluble sTREM2 in preventing AD pathogenesis. DISCUSSION: These findings demonstrate that TREM2 has at least two ligand-binding surfaces that might be therapeutic targets and uncovers a potential function for sTREM2 in directly inhibiting Aß polymerization.

4.
JCO Clin Cancer Inform ; 4: 824-838, 2020 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-32970484

RESUMEN

PURPOSE: To examine the impact of a clinical decision support system (CDSS) on breast cancer treatment decisions and adherence to National Comprehensive Cancer Center (NCCN) guidelines. PATIENTS AND METHODS: A cross-sectional observational study was conducted involving 1,977 patients at high risk for recurrent or metastatic breast cancer from the Chinese Society of Clinical Oncology. Ten oncologists provided blinded treatment recommendations for an average of 198 patients before and after viewing therapeutic options offered by the CDSS. Univariable and bivariable analyses of treatment changes were performed, and multivariable logistic regressions were estimated to examine the effects of physician experience (years), patient age, and receptor subtype/TNM stage. RESULTS: Treatment decisions changed in 105 (5%) of 1,977 patients and were concentrated in those with hormone receptor (HR)-positive disease or stage IV disease in the first-line therapy setting (73% and 58%, respectively). Logistic regressions showed that decision changes were more likely in those with HR-positive cancer (odds ratio [OR], 1.58; P < .05) and less likely in those with stage IIA (OR, 0.29; P < .05) or IIIA cancer (OR, 0.08; P < .01). Reasons cited for changes included consideration of the CDSS therapeutic options (63% of patients), patient factors highlighted by the tool (23%), and the decision logic of the tool (13%). Patient age and oncologist experience were not associated with decision changes. Adherence to NCCN treatment guidelines increased slightly after using the CDSS (0.5%; P = .003). CONCLUSION: Use of an artificial intelligence-based CDSS had a significant impact on treatment decisions and NCCN guideline adherence in HR-positive breast cancers. Although cases of stage IV disease in the first-line therapy setting were also more likely to be changed, the effect was not statistically significant (P = .22). Additional research on decision impact, patient-physician communication, learning, and clinical outcomes is needed to establish the overall value of the technology.

5.
BMC Womens Health ; 20(1): 194, 2020 Sep 05.
Artículo en Inglés | MEDLINE | ID: mdl-32891135

RESUMEN

BACKGROUND: To investigate the impact of the elevation of tumor-infiltrating lymphocytes (TILs) in different molecular subtypes of primary breast cancer, i.e. each 10% increment of TILs and high-level TILs (TILs≥50%) in tumor, on overall survival (OS) and pathological complete response (pCR) and to compare the presentation of high-level TILs across these molecular subtypes. METHODS: Citation retrieval was performed in the PubMed, Cochrane Library, Embase and Web of Science databases. All statistical calculations were performed by the software of StataSE version 12.0. RESULTS: Twenty-two eligible clinical trials including 15,676 unique patients were included for meta-analysis. Each 10% increment of TILs significantly improved OS in human epidermal growth factor receptor 2 (HER2)-overexpression (pooled Hazard ratio (HR), 0.92; 95% CI, 0.89-0.95) and triple-negative (TN) (pooled HR, 0.90; 95% CI, 0.89-0.92) breast tumors but not in luminal tumor subtype (pooled HR, 1.06; 95% CI, 0.99-1.13). It was also associated with an increased pCR rate in breast cancers (pooled Odds ratio (OR), 1.27; 95% CI, 1.19-13.5). High-level TILs were significantly related with a higher pCR rate (pooled OR, 2.73; 95% CI, 2.40-3.01) than low-level TILs. The HER2-amplified (pooled OR, 3.14; 95% CI, 1.95-5.06) and TN (pooled OR, 4.09; 95% CI, 2.71-6.19) phenotypes of breast cancers expressed significantly more high-level TILs than the luminal tumor subtype, although the presentation of those between the former two subsets was not significantly different (pooled OR, 1.30; 95%CI, 0.83-2.04). CONCLUSIONS: The elevation of TILs in breast tumors predicts favorable prognostic outcomes, particularly in the HER2-overexpression and TN subtypes.

6.
World J Surg Oncol ; 18(1): 243, 2020 Sep 11.
Artículo en Inglés | MEDLINE | ID: mdl-32917226

RESUMEN

BACKGROUND: To compare the efficacy of three types of palliative therapy for advanced hepatocellular carcinoma (HCC), including transarterial chemoembolisation (TACE) monotherapy, sorafenib alone and their combination. METHODS: The databases of PubMed, Embase and Cochrane Library were retrieved. The odds ratio (OR) with its 95% confidence interval (CI) was used to investigate the binary variables, and the standardised mean difference (SMD) with its 95% CI was employed to evaluate the continuous variables. All statistical tests were performed by using Stata/SE, version 12.0. RESULTS: Thirty-one clinical studies, containing 5125 unique cases of patients with advanced HCC, were included. There were significant improvements in overall survival (OS) (pooled SMD = 2.54; 95% CI 1.74-3.34) and time to progression (TTP) (pooled SMD = 2.49; 95% CI 0.87-4.12) of the patients after receiving the combination therapy of TACE and sorafenib, compared to TACE monotherapy, and the OS in the combined treatment cohort was also longer than that in the sorafenib-alone cohort (pooled SMD = 2.92; 95% CI 1.72-4.13). The combination therapy group in comparison to the TACE group benefited a significantly increased overall response rate (ORR) (pooled OR = 2.61; 95% CI 1.43-4.77), 1-year (pooled OR = 2.96; 95% CI 1.71-5.14) and 2-year (pooled OR = 1.64; 95% CI 1.18-2.28) survival rates and reduced disease progression rate (DPR) (pooled OR = 0.47; 95% CI 0.33-0.68); in parallel, the ORR in the group was also significantly higher than that in the sorafenib-alone group (pooled OR = 3.62; 95% CI 1.28-10.22), although without a difference in the DPR (pooled OR = 0.28; 95% CI 0.05-1.48). In addition, we discovered that the 1-year (pooled OR = 1.39; 95% CI 0.84-2.29) and 2-year (pooled OR = 1.70; 95% CI 0.69-4.18) survival rates in the TACE monotherapy cohort were not significantly different to those in the sorafenib-alone cohort. CONCLUSION: The combination therapy is more effective than monotherapy in improving the prognostic outcomes of patients with advanced HCC. Therefore, we recommend it as the preferred treatment intervention for those patients.

7.
ISA Trans ; 105: 77-85, 2020 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-32616355

RESUMEN

This paper presents vibration control analysis for a cantilever nanobeam system. The dynamics of the system is obtained by the non-local elastic relationship which characterizes the small scale effects. The boundary conditions and governing equation are respectively expressed by several ordinary differential equations (ODE) and a partial differential equation (PDE) with the help of the Hamilton's principle. Model-based control and adaptive control are both designed at the free end to regulate the vibration in the control section. By employing the Lyapunov stability approach, the system state can be proven to be substantiated to converge to zero's small neighbourhood with appropriate parameters. Simulation results illustrate that the designed control is feasible for the nanobeam system.

8.
Clin Breast Cancer ; 20(5): e589-e599, 2020 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-32565109

RESUMEN

PURPOSE: To investigate the prognosis of single hormone receptor-positive (HR+) breast cancer (estrogen receptor [ER] positive and progesterone receptor [PR] negative, and ER-PR+) compared to double HR+ (ER+PR+) and double HR- (ER-PR-) tumors. METHODS: We included 531,605 cases of invasive breast cancer between 1990 and 2012 from the US Surveillance, Epidemiology, and End Results (SEER) database for study and classified cases into 4 phenotypes according to expression of ER and PR: ER+PR+, ER+PR-, ER-PR+, and ER-PR-. RESULTS: Overall, 66,091 ER+PR- tumors and 9320 ER-PR+ tumors were identified. The clinical characteristics of the ER+PR- group were similar to those of the double HR+ group, while those of the ER-PR+ and double HR- groups were similar. Overall survival of patients with single HR+ tumors was intermediate between that of double HR+ and double HR- tumors. However, we observed no differences in disease-specific survival between ER-PR+ and ER-PR- patients. In multivariate analysis, outcomes were similar. Relative to the double HR+ patient group, risk of death in the ER+PR- group was higher (hazard ratio, 1.422, 95% confidence interval, 1.394-1.452). However, risk of death was comparable between ER-PR+ and ER-PR- patients (hazard ratio, 1.03; 95% confidence interval, 0.98-1.08). Multivariate Cox proportional analysis showed that survival times of patients in the younger age bracket (< 60 years), those positive for human epidermal growth factor receptor 2 (HER2), and patients with tumor stage I-III were longer in the ER-PR+ group. CONCLUSION: Disease-specific survival of single HR+ tumor cases was longer than that of double HR- tumors but poorer than double HR+ tumors. However, differences in disease-specific survival were not significant between the ER-PR+ and ER-PR- groups.

9.
Cell Death Dis ; 11(6): 457, 2020 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-32541667

RESUMEN

A further understanding of tumor angiogenesis is urgently needed due to the limited therapeutic efficacy of anti-angiogenesis agents. However, the origin of endothelial cells (EC) in tumors remains widely elusive and controversial. Snail has been thoroughly elucidated as a master regulator of the epithelial-mesenchymal transition (EMT), but its role in endothelium generation is not yet established. In this study, we reported a new and unexpected function of Snail in endothelium generation by breast cancer cells. We showed that high Snail-expressing breast cancer cells isolated from patients showed more endothelium generated from these cells. Expression of Snail was positively correlated with endothelial markers in breast cancer patients. The ectopic expression of Snail induced endothelial marker expression, tube formation and DiI-AcLDL uptake of breast cancer cells in vitro, and enhanced tumor growth and microvessel density in vivo. Snail-mediated endothelium generation depended on VEGF and Sox2. Mechanistically, Snail promoted the expression of VEGF and Sox2 through recruiting the p300 activator complex to these promoters. We showed the dual function of Snail in tumor initiation and angiogenesis in vivo and in vitro through activation of Sox2 and VEGF, suggesting Snail may be an ideal target for cancer therapy.

10.
Cell Biochem Biophys ; 78(2): 165-180, 2020 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-32441029

RESUMEN

We have previously described new pathways of vitamin D3 activation by CYP11A1 to produce a variety of metabolites including 20(OH)D3 and 20,23(OH)2D3. These can be further hydroxylated by CYP27B1 to produce their C1α-hydroxyderivatives. CYP11A1 similarly initiates the metabolism of lumisterol (L3) through sequential hydroxylation of the side chain to produce 20(OH)L3, 22(OH)L3, 20,22(OH)2L3 and 24(OH)L3. CYP11A1 also acts on 7-dehydrocholesterol (7DHC) producing 22(OH)7DHC, 20,22(OH)27DHC and 7-dehydropregnenolone (7DHP) which can be converted to the D3 and L3 configurations following exposure to UVB. These CYP11A1-derived compounds are produced in vivo and are biologically active displaying anti-proliferative, anti-inflammatory, anti-cancer and pro-differentiation properties. Since the protective role of the classical form of vitamin D3 (1,25(OH)2D3) against UVB-induced damage is recognized, we recently tested whether novel CYP11A1-derived D3- and L3-hydroxyderivatives protect against UVB-induced damage in epidermal human keratinocytes and melanocytes. We found that along with 1,25(OH)2D3, CYP11A1-derived D3-hydroxyderivatives and L3 and its hydroxyderivatives exert photoprotective effects. These included induction of intracellular free radical scavenging and attenuation and repair of DNA damage. The protection of human keratinocytes against DNA damage included the activation of the NRF2-regulated antioxidant response, p53-phosphorylation and its translocation to the nucleus, and DNA repair induction. These data indicate that novel derivatives of vitamin D3 and lumisterol are promising photoprotective agents. However, detailed mechanisms of action, and the involvement of specific nuclear receptors, other vitamin D binding proteins or mitochondria, remain to be established.

11.
Oncol Rep ; 44(1): 3-13, 2020 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-32319666

RESUMEN

The advent of targeted therapy for hormone receptor­positive/human epidermal growth factor receptor 2­negative advanced breast cancer (HR+/HER2­ aBC) provides a novel therapeutic approach other than endocrine therapy. One targeted signaling pathway and three immune­checkpoints have been demonstrated to be in association with tumor proliferation and growth in HR+/HER2­ aBC. A number of phosphoinositide 3­kinase/AKT/mammalian target of rapamycin signaling pathway inhibitors demonstrate clinical activity against this tumor subtype. The CDK4/6 inhibitors as a single agent or in combination with endocrine therapy have produced promising tumor response with acceptable toxicity in patients with HR+/HER2­ aBC. Programmed death 1/programmed death ligand 1 (PD1/PD­L1) and cytotoxic T lymphocyte antigen­4 inhibitors can also produce an antitumor immune response, which provides a proof­of­principle for the initial utilization of immunotherapy in breast cancer. The aim of the present review was to discuss the mechanisms of action, clinical efficacy and safety profiles of all the targeted biological therapies and immunotherapies that have been approved or are currently under evaluation for HR+/HER2­ aBC.

12.
Oncol Lett ; 19(3): 2085-2096, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-32194706

RESUMEN

The tremendous improvement of survival in patients with breast cancer can be attributed to several treatment strategies, but these strategies also lead to the occurrence of breast cancer-related lymphedema (BCRL). BRCL is regularly associated with factors such as axillary lymph node dissection and local lymph node radiotherapy and manifests as an increase of >10% in the volume of affected limbs. Being overweight or having obesity (body mass index ≥25 kg/m2), an excessive number of positive lymph nodes (>8) and capsular invasion by a tumor are additional risk factors for lymphedema. It is worth assessing the risk before surgery as this can prevent the occurrence of BCRL at the initial stage of breast cancer management. The clinical utility of many diagnostic tools and lymphedema surveillance allows early stage and even subclinical BCRL to be diagnosed, and allows real-time monitoring of the disease. The early diagnosis of BRCL allows treatment at an early stage, which is beneficial to the reduction of excess limb volume and the improvement of quality of life. At present, the major therapeutic methods of BCRL include complex decongestive therapy, pneumatic compression devices, participating in exercise, microsurgery and liposuction, each of which alleviates lymphedema effectively. No medications for treatment of BRCL have yet been developed. However, the recent findings on the success of molecular therapy in animal models may remedy this deficiency. Furthermore, the volume reduction of swollen limbs without swelling rebound by transplanting autologous stem cells has been successfully reported in some pilot studies, which may provide a new technique for treating BCRL. This review aimed to discuss the pathogenesis, clinical manifestation, risk factors, advantages and disadvantages of diagnostic tools, lymphedema surveillance and the characteristics of traditional and newly emerging BCRL treatments.

13.
Comput Biol Chem ; 85: 107228, 2020 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-32062378

RESUMEN

Calreticulin (CRT) is localized to and has functions in multiple cellular compartments, including the cell surface, the endoplasmic reticulum, and the extracellular matrix. Mutagenesis studies have identified several residues on a concave ß-sheet surface of CRT critical for CRT binding to carbohydrate and other proteins/peptides. How the mutations of these key residues in CRT affect the conformation and dynamics of CRT, further influencing CRT binding to carbohydrates and other proteins to signal the important biological activities remain unknown. In this study, we investigated the effect of three key point mutations (C105A, C137A and W319A) on CRT conformation and dynamics via atomistic molecular dynamics simulations. Results show that these three key residues mutations induced the changes of CRT local backbone flexibility and secondary structure of CRT N-domain, which could further affect CRT's binding activity. C137A mutation led to dramatic decrease of the overall size of CRT due to the P-domain fold back to the globular domain and formed new inter-domain contacts, which can cause blockage of CRT's binding with other large substrates. Furthermore, for CRT concave ß-strand surface patch containing lectin binding site, CRT C105A, C137A and W319A point mutation resulted in the changes in solvent accessible surface area, key residues' side chain atom positions and dynamical correlated motions between residues. All these changes could directly affect CRT binding behavior. Results of this study provide molecular and structural insights into understanding the role of key residues of CRT in its binding behavior.

14.
BMC Womens Health ; 20(1): 17, 2020 01 31.
Artículo en Inglés | MEDLINE | ID: mdl-32005117

RESUMEN

BACKGROUND: To investigate the efficacy of neoadjuvant chemotherapy (NCT), neoadjuvant endocrine therapy (NET) and neoadjuvant chemoendocrine therapy (NCET) on the tumour response, including pathological complete response (pCR) rate and overall response rate (ORR), in postmenopausal women with hormone receptor (HR)-positive breast cancer. METHODS: Based on a PRISMA-IPD statement, the PubMed, Embase and Cochrane Library databases were used to identify eligible trials published from inception to 7 May 2019. Pooled odds ratio (OR) with 95% confidential interval (CI) was calculated to assess the pCR rate and ORR of tumours among those three treatments via fixed- or random-effect Mantel-Haenszel models in terms of a Heterogeneity Chi2 test with a significant level of p < 0.1. All statistical tests were performed by the software of StataSE, version 12.0. RESULTS: The analysed data consisted of 10 eligible clinical trials with 971 unique HR-positive breast cancer patients. The pooled results indicated that the pCR rate of those patients undergoing NET was significantly lower than those undergoing NCT (pooled OR, 0.48; 95% CI, 0.26-0.90), whereas the difference of ORR between both therapies was not statistically significant (pooled OR, 1.05; 95% CI, 0.73-1.52). The combined paradigm of NCET compared with the monotherapy of NET or NCT did not present a significantly improved pCR rate or ORR (pooled OR, 2.61; 95% CI, 0.94-7.25; and 2.25; 95% CI, 0.39-13.05; respectively). CONCLUSION: Postmenopausal HR-positive breast cancer patients after NCT may have better tumour response than those after NET, while those undergoing NCET may not manifest the apparently improved clinical efficacies compared to those receiving monotherapy.


Asunto(s)
Antineoplásicos Hormonales/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Anciano , Neoplasias de la Mama/metabolismo , Quimioterapia Adyuvante , Femenino , Humanos , Persona de Mediana Edad , Terapia Neoadyuvante , Posmenopausia , Receptores Estrogénicos/metabolismo , Resultado del Tratamiento
15.
Biochim Biophys Acta Biomembr ; 1862(2): 183146, 2020 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-31816323

RESUMEN

Cell surface calreticulin (CRT) can mediate apoptotic cells removal by binding and activating LDL receptor-related protein (LRP1). Phosphatidylserine (PS) lipids in the inner leaflet of the cell membrane are externalized and become exposed in cholesterol (CHOL)-rich membrane raft-like microdomain during apoptosis and co-localized with cell surface CRT. How the apoptotic raft-like membrane microdomain affects the structure and dynamics of CRT, further affecting CRT binding with LRP1 to signal apoptotic-cell clearance, remains unknown. In this study, we investigate the interactions between CRT and raft-like bilayers with or without POPS lipids with molecular dynamics simulations. In addition, the effect of an apoptotic raft bilayer on the binding between CRT and thrombospondin-1 (TSP1), a ligand of CRT on the cell surface to signal focal adhesion disassembly, was also investigated. Results of single CRT interactions with raft-like bilayers show that PS lipids in apoptotic raft-like bilayer increased the interactions between CRT and lipid bilayer, which enhanced the conformational stability and increased dynamical motion of CRT. The microscopic and mesoscopic properties of apoptotic raft-like bilayer were altered by the binding of CRT with lipid bilayer. Results of CRT-TSP1 complex interactions with raft-like bilayers show that the binding free energy between TSP1 and CRT was reduced in apoptotic raft-like bilayer environment. This study provides molecular and structural insight into the effect of an apoptotic raft-like bilayer on the conformation and dynamics of CRT, which could enrich our understanding of CRT-mediated apoptotic-cell clearance and focal adhesion disassembly.


Asunto(s)
Apoptosis , Calreticulina/química , Membrana Dobles de Lípidos/química , Microdominios de Membrana/química , Simulación de Dinámica Molecular , Sitios de Unión , Calreticulina/metabolismo , Microdominios de Membrana/metabolismo , Fosfatidilserinas/química , Fosfatidilserinas/metabolismo , Unión Proteica , Trombospondinas/química , Trombospondinas/metabolismo
16.
Cancer Manag Res ; 11: 8043-8054, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31507328

RESUMEN

Purpose: To assess the overall survival (OS) of early human epidermal growth factor receptor 2 (HER2)-enriched breast cancer patients after receiving neoadjuvant trastuzumab (NAT) compared to adjuvant trastuzumab (AT) treatment and the difference in local-regional relapse (LRR) rate with this tumor and treatment between women after mastectomy and women after breast-conserving therapy (BCT). Methods: Articles were retrieved from PubMed, Embase, Web of Science, and Cochrane Library. A pooled odds ratio (OR) with a 95% confidential interval (CI) was calculated. The StataSE version 12.0 software was employed for meta-analysis. Results: Twelve available clinical studies containing 2366 subjects were included. The OS of NAT compared with that of AT was not significantly different (pooled OR=1.04; 95% CI, 0.47-2.33). There was a significantly lower LRR rate for patients with mastectomy compared to those with BCT (pooled OR=0.58; 95% CI, 0.38-0.89); however, subgroup analysis revealed that the significant advantage of LRR for mastectomy compared to BCT was only represented in women without trastuzumab treatment (pooled OR=0.52; 95% CI, 0.31-0.88) compared to those who received trastuzumab treatment (pooled OR=0.71; 95% CI, 0.34-1.49). Conclusion: Early stage HER2-overexpression breast cancer patients benefit with an equivalent OS from NAT treatment compared to AT. Patients who underwent mastectomy and BCT experienced a similar LRR rate if they received anti-HER2 targeted therapy of trastuzumab, but the LRR rate was discernibly reduced in patients who received mastectomy compared to BCT if they did not also receive trastuzumab treatment.

17.
JCO Clin Cancer Inform ; 3: 1-15, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-31419181

RESUMEN

PURPOSE: The aim of the current study was to assess treatment concordance and adherence to National Comprehensive Cancer Network breast cancer treatment guidelines between oncologists and an artificial intelligence advisory tool. PATIENTS AND METHODS: Study cases of patients (N = 1,977) who were at high risk for recurrence or who had metastatic disease and cell types for which the advisory tool was trained were obtained from the Chinese Society for Clinical Oncology cancer database (2012 to 2017). A cross-sectional observational study was performed to examine treatment concordance and guideline adherence among an artificial intelligence advisory tool and 10 oncologists with varying expertise-three fellows, four attending physicians, and three chief physicians. In a blinded fashion, each oncologist provided treatment advice on an average of 198 cases and the advisory tool on all cases (N = 1,977). Results are reported as rates and logistic regression odds ratios. RESULTS: Concordance for the recommended treatment was 0.56 for all physicians and higher for fellows compared with chief and attending physicians (0.68 v 0.54; 0.49; P = .001). Concordance differed by hormone receptor subtype-TNM stage, with the lowest for hormone receptor-positive human epidermal growth factor receptor 2/neu-positive cancers (0.48) and highest for triple-negative breast cancers (0.71) across most TNM stages. Adherence to National Comprehensive Cancer Network guidelines was higher for oncologists compared with the advisory tool (0.96 v 0.82; P < .003) and lower for fellows compared with attending physicians (0.93 v 0.98; 0.96; P = .04). CONCLUSION: Study findings reflect a complex breast cancer case mix, the limits of medical knowledge regarding optimum treatment, clinician practice patterns, and use of a tool that reflects expertise from one cancer center. Additional research in different practice settings is needed to understand the tool's scalability and its impact on treatment decisions and clinical and health services outcomes.


Asunto(s)
Inteligencia Artificial , Neoplasias de la Mama/terapia , Competencia Clínica , Sistemas de Apoyo a Decisiones Clínicas , Adhesión a Directriz , Oncólogos , Biomarcadores de Tumor , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/etiología , Toma de Decisiones Clínicas , Estudios Transversales , Femenino , Humanos , Oncología Médica/métodos , Estadificación de Neoplasias , Oncólogos/normas , Guías de Práctica Clínica como Asunto , Pautas de la Práctica en Medicina , Reproducibilidad de los Resultados
18.
Cancer Manag Res ; 11: 5765-5775, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31303789

RESUMEN

Radiotherapy can increase the cell cycle arrest that promotes apoptosis, reduces the risk of tumor recurrence and has become an irreplaceable component of systematic treatment for patients with breast cancer. Substantial advances in precise radiotherapy unequivocally indicate that the benefits of radiotherapy vary depending on intrinsic subtypes of the disease; luminal A breast cancer has the highest benefit whereas human epidermal growth factor receptor 2 (HER2)-positive and triple negative breast cancer (TNBC) are affected to a lesser extent irrespective of the selection of radiotherapy strategies, such as conventional whole-breast irradiation (CWBI), accelerated partial-breast irradiation (APBI), and hypofractionated whole-breast irradiation (HWBI). The benefit disparity correlates with the differential invasiveness, malignance, and radiosensitivity of the subtypes. A combination of a number of molecular mechanisms leads to the strong radioresistant profile of HER2-positive breast cancer, and sensitization to irradiation can be induced by multiple drugs or compounds in luminal disease and TNBC. In this review, we aimed to summarize the prognostic differences between various subtypes of breast tumors after CWBI, APBI, and HWBI, the potential reasons for drug-enhanced radiosensitivity in luminal breast tumors and TNBC, and the robust radioresistance of HER2-positive cancer.

19.
Medicine (Baltimore) ; 98(11): e14912, 2019 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-30882711

RESUMEN

BACKGROUND: To investigate and compare the effects of breast-conserving therapy (BCT) and mastectomy on the disease recurrence and long-term survival in early-stage luminal breast cancer and the difference in prognosis across diverse luminal subtypes receiving single surgical modality. METHODS: The databases of PubMed and Embase were retrieved to select eligible trials that were published from inception to 13 November 2018. The clinical trials that offered the details about recurrent disease and/or survival in luminal tumors underwent BCT or mastectomy met the inclusion criteria (n=24). With the random- or fixed-effect model basing on heterogeneity Chi test with its significant level of P < .1, pooled odds ratio (OR) with its 95% CI, and P value were identified for endpoints. RESULTS: The analyzed data were constituted of 25 qualified trials with 13,032 unique women suffered from luminal cancers. The fixed-effect models were utilized. On the LRR regarding BCT versus mastectomy, the pooled data indicated no significant difference in luminal carcinomas (OR, 0.84; 95%CI, 0.43-1.64; P = .61; n = 867). In BCT cohort, the pooled data showed that there were some significant benefits favoring luminal A over luminal B in LR (OR, 0.61; 95%CI, 0.46-0.81; P = .0007; n = 5406), DM (OR, 0.53; 95%CI, 0.41-0.69; P < .00001; n = 4662), DFS (OR, 0.59; 95%CI, 0.36-0.96; P = .03; n = 776) and OS (OR, 0.65; 95%CI, 0.42-0.99; P = .05; n = 1149), but not in LRR (OR, 0.74; 95%CI, 0.48-1.13; P = .16; n = 3732), coupled with luminal A/B over luminal-HER2 in LRR (OR, 0.43; 95%CI, 0.25-0.76; P = .004; n = 890), DM (OR, 0.56; 95%CI, 0.35-0.90; P = .02; n = 1396), DFS (OR, 0.47; 95%CI, 0.27-0.83; P = .009; n = 532); in mastectomy cohort, there were apparent advantages of LRR (OR, 0.58; 95%CI, 0.36-0.92; P = .02; n = 1768), LR (OR,0.56; 95%CI, 0.38-0.83; P = .004; n = 1209), DM (OR, 0.58; 95%CI, 0.40-0.84; P = .004; n = 652) and OS (OR, 0.62; 95%CI, 0.43-0.89; P = .009; n = 652) in luminal A vs luminal B. CONCLUSION: For early luminal breast cancer, the equality of LRR was achieved in BCT and mastectomy. In comparison, luminal A cancers benefit the most improved tumor re-appearence and survival in luminal diseases regardless of the option of surgical modality, whereas luminal-HER2 is affected by the worst clinical outcomes in them who follows BCT.


Asunto(s)
Neoplasias de la Mama/cirugía , Mastectomía/normas , Pronóstico , Resultado del Tratamiento , Adulto , Neoplasias de la Mama/epidemiología , Femenino , Humanos , Mastectomía/métodos , Mastectomía/estadística & datos numéricos
20.
Medicine (Baltimore) ; 98(6): e14407, 2019 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-30732191

RESUMEN

BACKGROUND: To integrate relevant clinical data of multicatheter accelerated partial breast irradiation (mAPBI) for reaching a comprehensive conclusion. METHODS: We did 3 meta-analyses for clinical outcomes including 1740 women from 4 articles, for acute radiotherapy (RT)-associated toxicity including 1255 patients from 5 articles, and for late RT-related toxicity involving 1565 patients from 9 papers. Clinical outcomes analyses were stratified by molecular subtypes, lymph nodes status, receptor status, and human epidermal growth factor receptor 2 (HER2) status. RESULTS: For the Luminal A/B phenotypes, the disease relapse and failure in survival significantly decreased when compared with triple negative (TN)/HER2-amplified subtypes (P < .00001). The 5-year regional nodal recurrence (RNR), 5-year distant metastasis-free survival (DMFS) and 5-year disease free-survival (DFS) of TN patients were significantly superior to HER2-overexpression patients (P < .00001). The 5-year cause-specific survival (CSS), 5-year DMFS and 5-year overall survival (OS) in women with lymph nodes-negative were significantly improved versus patients with lymph nodes-positive (P = .0001). Conversely, the positive status of HER2 compared with negative one significantly increased the rate of local recurrence (LR) (P = .02). For acute toxicity, the morbidity of dermatitis was significantly higher than hematoma and implant infection (P = .01, P < .0001, respectively). For late toxicity, the occurrences of fibrosis (32%) and telangiectasia (14%) were significantly higher than other complications (P < .0001). CONCLUSION: HER2-enriched subtype compared with other subtypes has significantly increased disease relapse and failure in survival. HER2-positive status is positively associated with an increased incidence of LR. Dermatitis is the most common acute RT-related toxicity and fibrosis is the first rife late RT-related toxicity.


Asunto(s)
Braquiterapia/mortalidad , Neoplasias de la Mama/radioterapia , Catéteres/efectos adversos , Traumatismos por Radiación/etiología , Traumatismos por Radiación/mortalidad , Adulto , Braquiterapia/instrumentación , Braquiterapia/métodos , Mama/patología , Mama/efectos de la radiación , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Supervivencia sin Enfermedad , Femenino , Humanos , Ganglios Linfáticos/patología , Ganglios Linfáticos/efectos de la radiación , Persona de Mediana Edad , Recurrencia Local de Neoplasia/etiología , Estadificación de Neoplasias , Receptor ErbB-2 , Resultado del Tratamiento
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