IntroductionA reliable risk stratification on the basis of tumor biology and host factors of HER2-positive (HER2+) early breast cancer (eBC) patients is needed. The aim of our study was to assess the prognostic role of body mass index (BMI) and hormone receptor (HR) expression in this setting.Patients and MethodsWe retrospectively evaluated 238 women with stage I to III HER2+ breast cancer who completed adjuvant chemotherapy (CHT) and 1 year of treatment with trastuzumab. The end point was 3-year distant disease-free survival (3yDDFS). Survival analysis was evaluated using the Kaplan–Meier method. Multivariate analysis was performed using Cox proportional-hazards model adjusting for HR status, BMI, tumor staging, size, nodal status, and type of adjuvant CHT. Association among categorical variables was assessed using χ2 test.ResultsThe early recurrence rate after 3 years resulted as 4.2% (40% HR+ patients and 60% HR− patients). Neither HR status nor BMI alone showed an association with 3yDDFS in multivariate analysis. However, the hazard ratios for patients with HR− tumors who had also BMI ≥25 (3yDDFS 86.9%; 95% confidence interval [CI], 75.0%-97.7%) were amplified compared with patients with HR+ tumors and with BMI <25 (3yDDFS 98%; 95% CI, 94.8%-100.0%) and other subgroups (P = .003). This observation was confirmed in multivariate analysis (hazard ratio, 1.79; 95% CI, 1.04-3.07; P = .03).ConclusionOur real-life data highlight a different risk of eBC recurrence after grouping patients according to HR status and BMI. These results might help clinicians to identify correct treatment strategies. Patients who are HR− and have BMI ≥25 might benefit from escalation approaches, whereas those who are HR+ and have BMI <25 might be eligible for a shorter duration of adjuvant treatment with anti-HER2 agents. 相似文献
Objectives: The current study aims to investigate the association between subjective social status (SSS) and prospective cognitive functioning of older adults and their spouses, and to explore the potential mediating roles of health habits and physical activities in this association.
Method: Using the longitudinal data of 512 pairs of community-dwelling older couples aged 65–91 years (M = 72.2 ± 4.6), we tested the effects of SSS in cognitive functioning using an Actor-Partner Interdependence Model. SSS was measured by a self-anchoring social ladder, and cognitive functioning was measured by the Mini-Mental State Examination at baseline and 4-year follow-up. Socioeconomic status (i.e. education) was tested as a moderator, and physical activity (measured by the Physical Activity Scale for the Elderly) as well as health habits (i.e. tobacco and alcohol consumption) were included as potential mediators.
Results: A partner effect of SSS was found only in the low-education group, in which the wife's higher level of SSS in the community was associated with the husband's better cognitive functioning in the follow-up. A small proportion of this effect was found to be partially mediated by participation in housework, such that the wife's higher SSS was associated with the husband's increased housework activity, which was related to higher prospective cognitive functioning.
Conclusion: By examining the dyadic effects of SSS with a longitudinal design, our findings extended the understanding on how subjective social status influenced older couples’ cognitive health, and provided evidence-based insights for future studies on cognitive health in later life. 相似文献
Dopaminergic neurotoxicity is characterized by damage and death of dopaminergic neurons. Parkinson's disease (PD) is a neurodegenerative disorder that primarily involves the loss of dopaminergic neurons in the substantia nigra. Therefore, the study of the mechanisms, as well as the search for new targets for the prevention and treatment of neurodegenerative diseases, is an important focus of modern neuroscience. PD is primarily caused by dysfunction of dopaminergic neurons; however, other neurotransmitter systems are also involved. Research reports have indicated that the glutamatergic system is involved in different pathological conditions, including dopaminergic neurotoxicity. Over the last two decades, the important functional interplay between dopaminergic and glutamatergic systems has stimulated interest in the possible role of metabotropic glutamate receptors (mGluRs) in the development of extrapyramidal disorders. However, the specific mechanisms driving these processes are presently unclear. The participation of the universal neuronal messenger nitric oxide (NO) in the mechanisms of dopaminergic neurotoxicity has attracted increased attention. The current paper aims to review the involvement of mGluRs and the contribution of NO to dopaminergic neurotoxicity. More precisely, we focused on studies conducted on the rotenone-induced PD model. This review is also an outline of our own results obtained using the method of electron paramagnetic resonance, which allows quantitation of NO radicals in brain structures. 相似文献
Objective: To investigate the effects of matrine on antigen presentation of dendritic cells (DCs), and to explore the pharmacological mechanism of matrine on anti-tumor effect. Methods: Different concentrations (0, 1, 2, 4, 8 and 16 μ g/mL) of matrine were co-cultured with DCs, the harvested DCs were co-cultured with antigens of Lewis lung cancer (LLC) cells, and then DCs and T cells were co-cultured to produce DCs-activated killer (DAK) cells, which have significant tumor-killing activity. The expression of cytokines, mRNA and protein of toll-like receptors (TLRs) in DCs were detected by enzyme linked immunosobent assay, polymerase chain reaction and Western blot, respectively. And the killing effect of DAK were measured by MTT assay. Results: Matrine significantly increased the mRNA expression of TLR7, TLR8, myeloid differentiation factor 88 (MyD88), tumor necrosis factor receptor-associated factor 6 (TRAF-6) and Iκ B kinase (IKK), as well as the protein expression of TLR7 and TLR8, and up-regulated the levels of interleukin-12 (IL-12), IL-6 and tumor necrosis factor-α (TNF-α ), meanwhile, it also increased the expressions of MHC-Ⅱ , CD54, CD80 and CD86 in DCs. DCs-activated effector T cells had significant tumor-killing activity. When the concentration of matrine was more than 4 μ g/mL, all indices had significant difference (P<0.01 or P<0.05). Conclusion: Matrine plays an anti-tumor role by regulating TLRs signal transduction pathway, promoting the secretion of inflammatory cytokines and enhancing immune function. 相似文献
The hormone melatonin connects environmental cues, such as photoperiod and temperature, with a number of physiological and behavioural processes, including seasonal reproduction, through binding to their cognate receptors. This study reports the structural, functional and physiological characterization of five high‐affinity melatonin receptors (Mtnr1aaα, Mtnr1aaβ, Mtnr1ab, Mtnr1al, Mtnr1b) in Atlantic salmon. Phylogenetic analysis clustered salmon melatonin receptors into three monophyletic groups, Mtnr1A, Mtnr1Al and Mtnr1B, but no functional representative of the Mtnr1C group. Contrary to previous studies in vertebrates, pharmacological characterization of four receptors in COS‐7, CHO and SH‐SY5Y cell lines (Mtnr1Aaα, Mtnr1Aaβ, Mtnr1Ab, Mtnr1B) showed induction of intracellular cAMP levels following 2‐iodomelatonin or melatonin exposure. No consistent response was measured after N‐acetyl‐serotonin or serotonin exposure. Melatonin receptor genes were expressed at all levels of the hypothalamo‐pituitary‐gonad axis, with three genes (mtnr1aaβ, mtnr1ab and mtnr1b) detected in the pituitary. Pituitary receptors displayed daily fluctuations in mRNA levels during spring, prior to the onset of gonadal maturation, but not in autumn, strongly implying a direct involvement of melatonin in seasonal processes regulated by the pituitary. To the best of our knowledge, this is the first report of cAMP induction mediated via melatonin receptors in a teleost species. 相似文献
Chimeric antigen receptor (CAR) T-cells treatment demonstrate the increasing and powerful potential of immunotherapeutic strategies, as seen mainly for hematological malignancies. Still, efficient CAR-T cell approaches for the treatment of a broader spectrum of tumors are needed. It has been shown that cancer cells can implement strategies to evade immune response that include the expression of inhibitory ligands, such as hypersialylated proteins (sialoglycans) on their surface. These may be recognized by sialic acid-binding immunoglobulin-type lectins (siglecs) which are surface receptors found primarily on immune cells. In this regard, siglec-7 and -9 are found on immune cells, such as natural killer cells, T-cells, and dendritic cells and they can promote immune suppression when binding to sialic acids expressed on target cells. In the present study, we hypothesized that it is possible to use genetically engineered T-cells expressing siglec-based CARs, enabling them to recognize and eliminate tumor cells, in a non-histocompatibility complex molecule restricted way. Thus, we genetically modified human T-cells with different chimeric receptors based on the exodomain of human siglec-7 and -9 molecules and selected optimal receptors. We then assessed their antitumor activity in vitro demonstrating the recognition of cell lines from different histologies. These results were confirmed in a tumor xenograft model exemplifying the potential of the present approach. Overall, this study demonstrates the benefit of targeting cancer-associated glycosylation patterns using CAR based on native immune receptors and expressed in human primary T-cells. 相似文献
IntroductionRecent reports on gene expression profiling (GEP) show several genes associated with malignant progression of GIST. However, genes associated with malignant transformation have not been clarified. Here, we aimed to reveal distinct genes in aggressive malignant GIST, using comprehensive gene expression analysis.Materials and methodsWe investigated GEP obtained by microarrays for 43 gastric GISTs, which mostly harbored KIT and PDGFRA mutations and integrated clinicopathological risk information. RT-PCR and immunohistochemistry were performed for FZD7, a receptor of Wnt ligands.ResultsGEP divided 43 gastric GISTs into two clusters. A cluster included seven of eight high-risk GISTs (88%) in modified NIH classification and was defined as high-risk cluster; the other cluster was defined as low-risk cluster. The number of probes with over 3-fold changes between the two clusters was 1,177, in which probes corresponding to 16 oncogenes were included. Genes involved in the Wnt signaling pathway were the most abundant among the 16 oncogenes. Focusing on 73 Wnt signaling pathway genes of the 21,578 probes, 12 upregulated and 5 downregulated genes were found in the high-risk cluster. Major cascade genes promoting the Wnt/β-catenin signaling pathway, including WNT11, FZD family, and DVL2, were upregulated in the high-risk cluster. SNAI1, SNAI2, and BIRC5, which are activated by this pathway and increase cell proliferation, were also upregulated. These gene expression alterations were consistent in the positive direction of this pathway. GISTs in high-risk cluster strongly expressed FZD7.ConclusionWnt/β-catenin signaling pathway may play an important role in malignant transformation of indolent GIST. 相似文献
Adrenoceptor and calcium channel modulating medications are widely used in clinical practice for acute neurological and systemic conditions. It is generally assumed that the cerebrovascular effects of these drugs mirror that of their systemic effects – and this is reflected in how these medications are currently used in clinical practice. However, recent research suggests that there are distinct cerebrovascular-specific effects of these medications that are related to the unique characteristics of the cerebrovascular anatomy including the regional heterogeneity in density and distribution of adrenoceptor subtypes and calcium channels along the cerebrovasculature. In this review, we critically evaluate existing basic science and clinical research to discuss known and putative interactions between adrenoceptor and calcium channel modulating pharmacotherapies, the neurovascular unit, and cerebrovascular anatomy. In doing so, we provide a rationale for selecting vasoactive medications based on lesion location and lay a foundation for future investigations that will define neuroprotective paradigms of adrenoceptor and calcium channel modulating therapies to improve neurological outcomes in acute neurological and systemic disorders. 相似文献