Research Mechanism and Progress of the Natural Compound Curcumin in Treating Alzheimer´s Disease.

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases. AD patients usually present symptoms, such as cognitive dysfunction, progressive memory loss, and other manifestations. With the increasing number of AD cases worldwide, there is an urgent need to develop effective drug treatments. Currently, drugs targeting AD symptoms may not change or prevent the progression of the disease. Curcumin, a polyphenol extracted from the turmeric herb, has been used for the treatment of AD. In this review, we summarized both cellular and animal studies and described the mechanism of action of curcumin in altering the pathological features of AD. Curcumin attenuates the formation of amyloid-ß plaques and promotes its decomposition, reduces the phosphorylation of tau, improves its clearance rate, and binds with copper to reduce cholesterol. It changes the activity of microglia, suppresses acetylcholinesterase, regulates insulin signal transduction, and exhibits antioxidant properties. Studies have found that curcumin can promote nerve repair and has a significant effect on AD. However, the low bioavailability of curcumin may hinder its use as a therapeutic agent. If this limitation can be overcome, curcumin may emerge as a promising drug for the treatment of AD.

Synthesis and evaluation of curcumin-based near-infrared fluorescent probes for detection of amyloid ß peptide in Alzheimer mouse models.

The abnormal accumulation of amyloid ß protein (Aß) is one of the most important causes of Alzheimer's disease (AD) and is usually a detecting biomarker. Curcumin and its derivatives have potential Aß aggregate targeting ability; we synthesized a series of curcumin-based near-infrared fluorescence probes in this study. By characterizing the excitation wavelength and emission wavelength, the imaging characteristics of the investigation in the near-infrared light region were determined; with an increase in the concentration of the probe compounds, the fluorescence intensity showed an upward trend, demonstrating ideal optical characteristics. In vivo, imaging results showed that the synthesized probe compounds could penetrate the blood-brain barrier (BBB) and specifically bind to Aß in the brain of APP/PS1 mice. Especially for compound 3b, the maximum emission wavelength was around 667 nm, and the fluorescence signal intensity in the brain of the APP/PS1 mice model was more than twice that of the wild control group at 120 min after administration, which could display Aß pathological changes. The fluorescent probes designed in this study can become an effective tool for early AD diagnosis and visual detection.

Gene expression profiling of circulating tumor cells captured by MicroCavity Array is superior to enumeration in demonstrating therapy response in patients with newly diagnosed advanced and locally advanced non-small cell lung cancer.

Background: Circulating tumor cells (CTCs) are a promising non-invasive tool for monitoring therapy response. The only Food and Drug Administration (FDA)-approved test is limited to enumeration of epithelial CTC without further characterization and is not approved for the management of non-small cell lung cancer (NSCLC). Here we use a MicroCavity Array (MCA) system to capture CTC agnostic of epithelial markers for further molecular testing in NSCLC. Methods: CTCs were enumerated by fluorescent microscopy as longitudinal sampling throughout disease management from 213 NSCLC patients. CTC-enriched samples from a subset of 127 patients were interrogated for gene expression by reverse transcription polymerase chain reaction (RT-PCR) using a customized pre-selected panel of 20 genes. Results: At least 1 CTC was detected by enumeration in 53.8% of samples. Most patients had fewer than 5 CTCs (91%) and the highest observed count was 35 CTCs. Enumeration of single CTCs was not prognostic, although detection of CTC clusters at any time point was associated with increased risk of progression [hazard ratio (HR) 3.00, 95% confidence interval (CI): 1.1-8.2, P=0.0318]. In contrast, 124 (97.6%) patients with samples interrogated for gene expression had at least 1 gene detectable in at least 1 sample, and 101 (79.5%) had at least one elevated epithelial gene in at least one timepoint. High expression of BCL2, CD274 [programmed death-ligand 1 (PD-L1)], CDH1, EPCAM, FGFR1, FN1, KRT18, MET and MUC1 were associated with poor prognosis. Patients with CTCs positive for at least 3 epithelial genes at baseline all progressed within 10 months (HR 8.2, P<0.001, 95% CI: 3.2-21.1). BCL2, CD274 (PD-L1), EPCAM and MUC1 remained significant independent prognostic factors in multivariate, time-dependent analyses of progression and death. Conclusions: The selective profile of CTC genes and identification of CTC clusters better correlated with prognosis than enumeration of enriched CTC in NSCLC patients in this study.

Preparation, properties, applications and outlook of graphene-based materials in biomedical field: a comprehensive review.

Graphene, the world's thinnest two-dimensional (2D) carbon material, with the highly ordered and repeated atomic structure and its excellent properties such as mechanical, electrical, optical, chemical, and thermal properties, has been extensively studied and applied in materialogy, physics, biomedicine and other fields in recent years. In the case of biomedical applications, the advent of graphene-based materials (GBMs) has resulted in excellent biomedical materials with a wide range of applications. Compared with the published reviews of graphene-based biomedical materials, we systematically and comprehensively introduced the properties of graphene-based biomaterials from the perspective of biomedical applications. In addition, we introduced the structure and preparation methods of graphene and its derivatives, and summarized recent advances on GBMs in the biomedical field, including drug carriers, biosensors, tissue engineering, antimicrobial materials, and other forms of exploration for medical heating, radiation shielding, surgical suturing, and wastewater treatment. Finally, we discussed the current problems and challenges of GBMs and the prospect for the future development in the biomedical field.

Final efficacy outcomes of atezolizumab with chemoradiation for unresectable NSCLC: The phase II DETERRED trial.

INTRODUCTION: The phase II DETERRED trial assessed the safety and efficacy of consolidation and concurrent immunotherapy with chemoradiation in unresectable locally advanced non-small cell lung cancer. We present updated efficacy analysis of this trial. METHODS: The trial was conducted in 2 parts with patients in part 1 (n = 10) receiving chemoradiation with consolidation atezolizumab, while patients in part 2 (n = 30) received concurrent and consolidation atezolizumab. Progression-free survival (PFS), time to second progression (PFS2), and overall survival (OS) were assessed using Kaplan-Meier analysis. Subset analyses were performed by programmed cell death ligand-1 (PD-L1) status and targetable driver oncogene mutation status. RESULTS: At a median follow-up of 39.2 months, the median PFS for part 1 was 18.9 months and 15.1 months for part 2. Median OS for part 1 was 26.5 months and was not reached for part 2. For the cohort, 3-year OS was 53.8%, while 4-year OS was 47.4%. Patients with targetable driver oncogene mutations had a median PFS of 9.4 months and OS of not reached compared to 16.6 months (HR: 3.49, p = 0.02) and 26.9 months (HR: 0.40, p = 0.12) respectively compared to those without targetable driver oncogene mutations. Patients with PD-L1 < 1% had median PFS of 11.0 months and OS of 26.5 months compared to 27.4 months (HR: 2.01, p = 0.10) and not reached (HR: 1.49, p = 0.41) respectively for those with PD-L1 ≥ 1%. CONCLUSIONS: In the DETERRED trial, chemoradiation with concurrent and/or consolidative atezolizumab led to comparable efficacy as consolidative durvalumab in the PACIFIC trial. The presence of targetable driver oncogene mutations led to worse PFS, while PD-L1 < 1% trended to worse PFS.

Phase I Trial of Definitive Concurrent Chemoradiotherapy and Trametinib for KRAS-Mutated Non-Small Cell Lung Cancer.

OBJECTIVE: This phase I trial (NCT01912625) evaluated the safety and pharmacokinetics of definitive concurrent chemoradiotherapy (cCRT) and the radiosensitizer trametinib (MEK1/2 inhibitor) for KRAS-mutated nonmetastatic non-small cell lung cancer (NSCLC). METHODS: Patients received cCRT (carboplatin/paclitaxel and 60 Gy/30 fractions radiotherapy); oral trametinib (7 days/week) commenced on day 1 and completed on the final day of radiotherapy. Dose-finding of trametinib was done using the time-to-event continual reassessment method (TiTE-CRM); dose levels were 0.5mg (level -1), 1mg (initial, level 1), 1.5mg (level 2), and 2mg (level 3). Progression-free (PFS) and overall survival (OS) times were also recorded. RESULTS: Fifteen patients (stage III, variety of KRAS mutations) were treated, with 1/5/4/5 at dose levels -1/1/2/3, respectively. Five patients received dose reductions (n=2, levels 2 and 3; n=1, level 1). Twelve patients completed the full cCRT course. One patient (following 12d trametinib) was taken off protocol for an unrelated/unresolved grade 1 event and later experienced grade 5 sepsis/respiratory failure. There was one grade 4 retinal detachment; grade 3 events included skin rash (n=2) and ventricular dysfunction, pneumonitis, pain, fatigue, and diarrhea (n=1 each). The final dose selected by the TiTE-CRM of trametinib was 1.5 mg. Pharmacokinetic profiles were elucidated and extensively described. At median follow-up of 70 months, median PFS was 11 months and median OS was 38 months. CONCLUSIONS: The MTD for trametinib when combined with cCRT is 1.5 mg, with encouraging preliminary outcomes. This combination merits further study to combine with consolidation durvalumab in non-metastatic KRAS mutant NSCLC.

Enumeration and molecular characterization of circulating tumor cells enriched by microcavity array from stage III non-small cell lung cancer patients.

BACKGROUND: Various methods of liquid biopsy through the sampling of blood in cancer patients allow access to minuscule amounts of tumor that can easily be sampled repeatedly throughout therapy. Circulating tumor cells (CTCs) represent shed tumor cells that can be characterized by imaging or molecular techniques using an amenable enrichment platform. Here we validate the Hitachi Chemical Micro Cavity Array (MCA) for the enrichment of CTCs from the blood of patients diagnosed with stage III non-small cell lung cancer (NSCLC). MCA is a semi-automated filtration system that enriches CTCs on the basis of size and membrane deformability rather than a biased selection of surface antigens. METHODS: CTCs were enriched from the peripheral blood of 38 patients diagnosed with stage III NSCLC at the start of chemoradiation. Two tubes of EDTA blood were collected from each patient and processed through MCA in parallel. In the first tube, CTCs were identified as pan-cytokeratin (CK)+ CD45- nucleated cells and enumerated. The second tube was depleted of leukocytes using CD45 antibody-coated magnetic microbeads before enrichment by MCA, followed by quantitative reverse transcription polymerase chain reaction (qRT-PCR) to interrogate CTC-enriched lysates for expression of 16 target mRNAs from a panel of epithelial, mesenchymal, stem-like, and cancer signaling-related genes. CTC-enriched lysates from similarly prepared peripheral blood samples from 18 healthy donors were used to define positive gene expression. RESULTS: CTCs were identified by imaging in 30 of 38 patient samples (79%). At least 1 target gene was positively expressed in 23 of 25 (92%) patient samples that was subjected to molecular characterization. A CTC count of ≥7 was associated with poor progression-free survival (PFS) [hazard ratio (HR) 4.24, 95% confidence interval (CI), 1.73-10.40, P=0.020] and poor overall survival (HR 8.17, 95% CI, 2.87-23.26, P<0.001). Expression of BCL2 by MCA-enriched CTCs was associated with poor PFS (HR 3.11, 95% CI, 1.18-8.22, P=0.022). Individually, CTC count and expression of BCL2 each remained statistically significant predictors of disease progression and overall survival in multivariate analysis. CONCLUSIONS: This is the first demonstration that lysates of MCA-enriched CTCs are amenable to molecular characterization. CTCs enriched by MCA are an independent prognostic marker in NSCLC.

Randomized Phase IIB Trial of Proton Beam Therapy Versus Intensity-Modulated Radiation Therapy for Locally Advanced Esophageal Cancer.

PURPOSE: Whether dosimetric advantages of proton beam therapy (PBT) translate to improved clinical outcomes compared with intensity-modulated radiation therapy (IMRT) remains unclear. This randomized trial compared total toxicity burden (TTB) and progression-free survival (PFS) between these modalities for esophageal cancer. METHODS: This phase IIB trial randomly assigned patients to PBT or IMRT (50.4 Gy), stratified for histology, resectability, induction chemotherapy, and stage. The prespecified coprimary end points were TTB and PFS. TTB, a composite score of 11 distinct adverse events (AEs), including common toxicities as well as postoperative complications (POCs) in operated patients, quantified the extent of AE severity experienced over the duration of 1 year following treatment. The trial was conducted using Bayesian group sequential design with three planned interim analyses at 33%, 50%, and 67% of expected accrual (adjusted for follow-up). RESULTS: This trial (commenced April 2012) was approved for closure and analysis upon activation of NRG-GI006 in March 2019, which occurred immediately prior to the planned 67% interim analysis. Altogether, 145 patients were randomly assigned (72 IMRT, 73 PBT), and 107 patients (61 IMRT, 46 PBT) were evaluable. Median follow-up was 44.1 months. Fifty-one patients (30 IMRT, 21 PBT) underwent esophagectomy; 80% of PBT was passive scattering. The posterior mean TTB was 2.3 times higher for IMRT (39.9; 95% highest posterior density interval, 26.2-54.9) than PBT (17.4; 10.5-25.0). The mean POC score was 7.6 times higher for IMRT (19.1; 7.3-32.3) versus PBT (2.5; 0.3-5.2). The posterior probability that mean TTB was lower for PBT compared with IMRT was 0.9989, which exceeded the trial's stopping boundary of 0.9942 at the 67% interim analysis. The 3-year PFS rate (50.8% v 51.2%) and 3-year overall survival rates (44.5% v 44.5%) were similar. CONCLUSION: For locally advanced esophageal cancer, PBT reduced the risk and severity of AEs compared with IMRT while maintaining similar PFS.

Phase II Trial of Concurrent Atezolizumab With Chemoradiation for Unresectable NSCLC.

INTRODUCTION: Consolidation durvalumab after chemoradiation (CRT) is the current standard of care for locally advanced NSCLC. We hypothesized that adding immunotherapy concurrently with CRT (cCRT) would increase efficacy without additive toxicity. METHODS: This phase II study was conducted in two parts. Part 1 (n = 10) involved administration of conventionally fractionated CRT followed by consolidation chemotherapy (atezolizumab [two cycles] and maintenance atezolizumab up to 1 y). Part 2 (n = 30) involved administration of cCRT with atezolizumab followed by the same consolidation and maintenance therapies as in part 1. Programmed cell death ligand-1 staining cutoffs (1% or 50%) using Dako 22C3 immunohistochemistry were correlated with clinical outcomes. RESULTS: The overall toxicities for part 1/2 were overall adverse events of grade 3 and above of 80%/80%; immune-related adverse events of grade 3 and above of 30%/20%; and pneumonitis of grade 2 and above of 10%/16%, respectively. In part 1, for preliminary efficacy results, with a median follow-up of 22.5 months, the median progression-free survival was 18.6 months, and the overall survival was 22.8 months. In part 2, with a median follow-up time of 15.1 months, the median progression-free survival was 13.2 months, and the overall survival was not reached. There was no difference in cancer recurrence regardless of programmed cell death ligand-1 status. CONCLUSIONS: Atezolizumab with cCRT is safe and feasible and has no added toxicities compared with historical rates.

CDK11(p58) protein kinase activity is associated with Bcl-2 down-regulation in pro-apoptosis pathway.

CDK11(p58), a G2/M-specific protein kinase, has been shown to be associated with apoptosis in many cell lines, with largely unknown mechanisms. Our previous study proved that CDK11(p58)-enhanced cycloheximide (CHX)-induced apoptosis in SMMC-7721 hepatocarcinoma cells. Here we report for the first time that ectopic expression of CDK11(p58) down-regulates Bcl-2 expression and its Ser70, Ser87 phosphorylation in CHX-induced apoptosis in SMMC-7721 cells. Overexpression of Bcl-2 counteracts the pro-apoptotic activity of CDK11(p58). Furthermore, we confirm that the kinase activity of CDK11(p58) is essential to the down-regulation of Bcl-2 as well as apoptosis. Taken together, these results demonstrate that CDK11(p58) down-regulates Bcl-2 in pro-apoptosis pathway depending on its kinase activity, which elicits survival signal in hepatocarcinoma cells.

Induction of apoptosis by p110C requires mitochondrial translocation of the proapoptotic BCL-2 family member BAD.

p110C, a 50-kDa isoform of the PITSLRE kinase family, was demonstrated to play an important role in cell apoptosis. However, how p110C exactly promotes apoptosis is unclear. Our previous study showed that p110C interacted with p21-activated kinase 1 (PAK1), an important kinase of the proapoptotic BCL-2 family member BAD, and evidently inhibited its kinase activity. Here, we report that overexpression of p110C leads to decreased phosphorylation of BAD and its subsequent translocation from cytosol to mitochondria, which in turn induces the release of cytochrome c and the onset of apoptosis. Knocking down endogenous BAD expression will inhibit p110C induced apoptosis. Two kinase dead forms of p110C, D149N and K36N, lose the ability to inhibit the kinase activity of PAK1 and fail to induce the translocation of BAD and the BAD and such proapoptotic ability is associated with the kinase activity of p110C.

Identification of extracellular signal-regulated kinase 3 as a new interaction partner of cyclin D3.

Cyclin D3, like cyclin D1 and D2 isoforms, is a crucial component of the core cell cycle machinery in mammalian cells. It also exhibits its unique properties in many other physiological processes. In the present study, using yeast two-hybrid screening, we identified ERK3, an atypical mitogen-activated protein kinase (MAPK), as a cyclin D3 binding partner. GST pull-down assays showed that cyclin D3 interacts directly and specifically with ERK3 in vitro. The binding of cyclin D3 and ERK3 was further confirmed in vivo by co-immunoprecipitation assay and confocal microscopic analysis. Moreover, carboxy-terminal extension of ERK3 was responsible for its association with intact cyclin D3. These findings further expand distinct roles of cyclin D3 and suggest the potential activity of ERK3 in cell proliferation.