Alzheimer's disease (AD) is a chronic and progressive neurodegenerative disease of central nervous system (CNS). Nowadays, increasing evidence suggests that immune system plays a significant role in the mechanisms of AD's onset and progression. Microglia, the main participator in the immune system of CNS, is always regarded as a protector of our brain in a healthy state and also has a beneficial role in maintaining the homeostasis of CNS microenvironment. However, chronic and sustained stimulation can push microglia into the state termed priming. Primed microglia can induce the production of amyloid β (Aβ), tau pathology, neuroinflammation and reduce the release of neurotrophic factors, resulting in loss of normal neurons in quantity and function that has immense relationship with AD. The therapeutic strategies mainly aimed at modulating the microenvironment and microglial activity in CNS to delay progression and alleviate pathogenesis of AD. Overall, in this review, we highlight the mechanism of microglial priming, and discuss the profound relationship between microglial priming and AD. Besides, we also pay attention to the therapeutic strategies targeting at microglial priming.
Efficacy data from the KATHERINE clinical trial, comparing the HER2-directed antibody-drug conjugate (ADC) ado-trastuzumab emtansine (T-DM1) to trastuzumab in patients with early-stage HER2-amplified/overexpressing breast cancer with residual disease after neoadjuvant therapy, demonstrates superiority of T-DM1 (HR for invasive disease or death, 0.50; P < 0.001). This establishes foundational precedent for ADCs as effective therapy for treatment of subclinical micrometastasis in an adjuvant (or post-neoadjuvant) early-stage solid tumor setting. Despite this achievement, general principles from proposed systems pharmacokinetic modeling for intracellular processing of ADCs indicate potential shortcomings of T-DM1: (i) C max limited by toxicities; (ii) slow internalization rate; (iii) resistance mechanisms due to defects in intracellular trafficking [loss of lysosomal transporter solute carrier family 46 member 3, (SLC46A3)], and increased expression of drug transporters MDR1 and MRP1; and (iv) lack of payload bystander effects limiting utility in tumors with heterogeneous HER2 expression. These handicaps may explain the inferiority of T-DM1-based therapy in the neoadjuvant and first-line metastatic HER2 þ breast cancer settings, and lack of superiority to chemotherapy in HER2 þ advanced gastric cancer. In this review, we discuss how each of these limitations is being addressed by manipulating internalization and trafficking using HER2:HER2 bispecific or biparatopic antibody backbones, using site-specific, fixed DAR conjugation chemistry, and payload swapping to exploit alternative intracellular targets and to promote bystander effects. Newer HER2-directed ADCs have impressive clinical activity even against tumors with lower levels of HER2 receptor expression. Finally, we highlight ongoing clinical efforts to combine HER2 ADCs with other treatment modalities, including chemotherapy, molecularly targeted therapies, and immunotherapy.
BackgroundDuctal carcinoma in situ with microinvasion (DCIS-Mi) generally has favorable prognosis, but the long-term outcomes of DCIS-Mi and the biologic evolution from ductal carcinoma in situ (DCIS), DCIS-Mi, to DCIS with T1a breast cancer (DCIS-T1a) has not been specified. The aim of our study was to explore the biological and prognostic features of DCIS-Mi, compared with pure DCIS and DCIS-T1a.ResultsAfter a median follow-up of 31 months, the 3-year estimated disease free survival(DFS) rate of DCIS-Mi patients was significantly lower than that of pure DCIS patients (89.5% vs 97.1%, P=0.009). Patients with DCIS-Mi or DCIS-T1a tumors had comparable 3-year estimated DFS rates (89.5% vs 94.3%, P=0.13). No significant difference in overall survival (OS) was found among different groups (99.6%, 100% and 99.1% for DCIS, DCIS-Mi and DCIS-T1a, P=0.797). In chemotherapy and trastuzumab-naive DCIS-Mi patients, human epidermal growth factor receptor2 (HER2) positivity (HR=21.8, 95%CI, 1.7-286.8, P=0.019) were independent predictor of worse DFS on multivariate analysis.MethodsDuring September 2002 and December 2014, 602 breast cancer patients who underwent radical surgery were retrospectively reviewed. Three hundred and fifty-nine patients (59.6%) had pure DCIS, 84(14.0%) and 159(26.4%) were diagnosed as DCIS-Mi and DCIS-T1a. Clinico-pathological features were compared between different subgroups.ConclusionsDCIS-Mi displayed a comparable survival to that of DCIS-T1a and a more aggressive biological nature than pure DCIS. Patients with HER2-positive DCIS-Mi had a worse survival and adjuvant chemotherapy plus target therapy needs to be further optimized in those patients.
PurposeFew studies has documented early relapse in luminal B/HER2-negative breast cancer. We examined prognostic factors for early relapse among these patients to improve treatment decision-making.Patients and MethodsA total 398 patients with luminal B/HER2-negative breast cancer were included. Kaplan-Meier curves were applied to estimate disease-free survival and Cox regression to identify prognostic factors.ResultsProgesterone receptor (PR) negative expression was associated with higher tumor grade (p<.001) and higher Ki-67 index (p = .010). PR-negative patients received more chemotherapy than the PR-positive group (p = .009). After a median follow-up of 28 months, 17 patients (4.3%) had early relapses and 8 patients (2.0%) died of breast cancer. The 2-year disease-free survival was 97.7% in the PR-positive and 90.4% in the PR-negative groups (Log-rank p = .002). Also, patients with a high Ki-67 index (defined as >30%) had a reduced disease-free survival (DFS) when compared with low Ki-67 index group (≤30%) (98.0% vs 92.4%, respectively, Log-rank p = .013). In multivariate analysis, PR negativity was significantly associated with a reduced DFS (HR = 3.91, 95% CI 1.29–11.88, p = .016).ConclusionIn this study, PR negativity was a prognostic factor for early relapse in luminal B/HER2-negative breast cancer, while a high Ki-67 index suggested a higher risk of early relapse.
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