Toward better understanding and management of chemobrain: the potential utilities of the MemTrax memory test.

OBJECTIVE: To study the effects of chemotherapy on cognitive function in breast cancer patients, and to investigate the relationship of MemTrax test of memory and related functions to the FACT-Cog functional self-assessment for the evaluation and management of chemobrain. METHODS: In this prospective cohort study, clinical information of pathologically confirmed female breast cancer patients who decided to receive chemotherapy were collected in a questionnaire which was developed for this study and provided as a supplementary file. The FACT-Cog self-assessment and MemTrax test were administered before and after the chemotherapy treatments. Patients with chemobrain were identified using published criteria based on FACT-Cog scores, and MemTrax scores from chemobrain patients were analyzed. RESULTS: Fifty-six patients participated in this study, of which 41 participants completed 4 or more cycles of chemotherapy and were included in the final analyses here. Using the reported high end of minimal clinical differences (10.6 points) of FACT-Cog before and after chemotherapy, 18 patients suffered from chemobrain in this study. In these 18 chemobrain patients, no cognitive impairments were detected by MemTrax, which paradoxically demonstrated an improvement in the normal cognitive range. CONCLUSION: The cognitive impairment induced by chemotherapy in breast cancer patients is detectable by the FACT-Cog in a Chinese cohort but is not detected by the MemTrax memory test. The fact that the more objective MemTrax could not detect the impairment could alleviate patients' concerns which in turn would be beneficial for patients' mental health.

Risk factors for cardiac rupture after acute ST-segment elevation myocardial infarction during the percutaneous coronary intervention era: a retrospective case-control study.

Background: In percutaneous coronary intervention (PCI) era, more clinically valuable risk factors are still needed to determine the occurrence of cardiac rupture (CR). Therefore, we aimed to provide evidence for the early identification of CR in ST-segment elevation myocardial infarction (STEMI). Methods: A total of 22,016 consecutive patients with STEMI admitted to Cangzhou Central Hospital and Tianjin Chest Hospital from January 2013 to July 2021 were retrospectively included, among which 195 patients with CR were included as CR group. From the rest 21,820 STEMI patients without CR, 390 patients at a ratio of 1:2 were included as the control group. A total of 66 patients accepted PCI in the CR group, and 132 patients who accepted PCI in the control group at a ratio of 1:2 were included. The status of first medical contact, laboratory examinations, and PCI characteristics were recorded. Multivariate logistic regression analysis was used to investigate the risk factors related to CR. Results: There was a higher proportion of patients with myocardial infarction (MI) in the high lateral wall in the CR group (23.6% vs. 8.2%, P<0.001). The proportion of single lesions was lower in the CR group (24.2% vs. 45.5%, P=0.004). Female (OR =2.318, 95% CI: 1.431-3.754, P=0.001), age (OR =1.066, 95% CI: 1.041-1.093, P<0.001), smoking (OR =1.750, 95% CI: 1.086-2.820, P=0.022), total chest pain time (OR =1.017, 95% CI: 1.000-1.035, P=0.049), recurrent acute chest pain (OR =2.750, 95% CI: 1.535-4.927, P=0.001), acute myocardial infarction (AMI) in the high lateral wall indicated by ECG (OR =5.527, 95% CI: 2.798-10.918, P<0.001), acute heart failure (OR =3.585, 95% CI: 2.074-6.195, P<0.001), and NT-proBNP level (OR =1.000, 95% CI: 1.000-1.000, P=0.023) were risk factors for CR in all patients. In patients who accepted PCI, single lesion (OR =0.421, 95% CI: 0.204-0.867, P=0.019), preoperative thrombolysis in myocardial infarction (TIMI) grade (OR =0.358, 95% CI: 0.169-0.760, P=0.007), and postoperative TIMI grade (OR =0.222, 95% CI: 0.090-0.546, P=0.001) were risk factors for CR. Conclusions: Non-single lesions and preoperative and postoperative TIMI grades were risk factors for CR in patients who accepted PCI. In addition to previously reported indicators, we found that AMI in the high lateral wall maybe helpful in early and accurate identification and prevention of possible CR.

Now is the Time to Improve Cognitive Screening and Assessment for Clinical and Research Advancement.

Wang et al. analyze Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment accuracy as screening tests for detecting dementia associated with Alzheimer's disease (AD). Such tests are at the center of controversy regarding recognition and treatment of AD. The continued widespread use of tools such as MMSE (1975) underscores the failure of advancing cognitive screening and assessment, which has hampered the development and evaluation of AD treatments. It is time to employ readily available, efficient computerized measures for population/mass screening, clinical assessment of dementia progression, and accurate determination of approaches for prevention and treatment of AD and related conditions.

miR-122 promotes diabetic retinopathy through targeting TIMP3.

Diabetic retinopathy (DR) is a primary complication of diabetes mellitus. DR can cause severe vision loss for patients. miR-122 is elevated in DR patients, while its role in DR is unclear. Hence, the purpose of this study was to analyze the effect of miR-122 on the function of high glucose-induced REC cells and the underlying molecular mechanisms. In this study, our results revealed that miR-122 was up-regulated in high glucose-induced human retinal pigment epithelial cells (ARPE-19). High glucose decreased the cell viability of ARPE-19 cells, which was then restored by miR-122 knockdown. In addition, miR-122 knockdown suppressed apoptosis of high glucose-induced ARPE-19 cells. High glucose also inhibited B-cell lymphoma-2 (Bcl-2) level and increased cleaved caspase-3 level in ARPE-19 cells, which were reversed by miR-122 knockdown. Tissue inhibitor of metalloproteinases-3 (TIMP3) was a direct target of miR-122. TIMP3 was decreased in high glucose-induced ARPE-19 cells, and the decrease was abrogated by miR-122 knockdown. In addition, the effects of miR-122 overexpression in cell viability and apoptosis of high glucose-induced ARPE-19 were abolished by overexpression of TIMP3. In conclusion, the effect and mechanism of miR-122 on high glucose-induced ARPE-19 cells were demonstrated for the first time. miR-122 promoted diabetic retinopathy through targeting TIMP3, making miR-122 a promising target for diabetic retinopathy therapy.

Identification of 5-(1-Methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)thiophene-2-Carboxamides as Novel and Selective Monoamine Oxidase B Inhibitors Used to Improve Memory and Cognition.

Initial work in Drosophila and mice demonstrated that the transcription factor cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) is a master control gene for memory formation. The relationship between CREB and memory has also been found to be true in other species, including aplysia and rats. It is thus well-established that CREB activation plays a central role in memory enhancement and that CREB is activated during memory formation. On the basis of these findings, a phenotypic high-throughput screening campaign utilizing a CRE-luciferase (CRE-Luci) SK-N-MC cell line was performed to identify compounds that enhance transcriptional activation of the CRE promoter with a suboptimal dose of forskolin. A number of small-molecule hits of unknown mechanisms of action were identified in the screening campaign, including HT-0411. Follow-up studies suggested that the CREB activation by HT-0411 is attributed to its specific and selective inhibition of monoamine oxidase B (MAO-B). Further, HT-0411 was shown to improve 24 h memory in rodents in a contextual fear conditioning model. This report describes the lead optimization of a series of 5-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl) thiophene-2-carboxamides that were identified as novel, potent, and selective inhibitors of MAO-B. Extensive SAR studies and in vivo behavioral evaluations of this and other related analogue series identified a number of potential clinical development candidates; ultimately, compound 8f was identified as a candidate molecule with high selectivity toward MAO-B (29-56 nM) over MAO-A (19% inhibition at a screening concentration of 50 µM), an excellent profile against a panel of other enzymes and receptors, good pharmacokinetic properties in rodents and dogs, and efficacy in multiple rodent memory models.

Sialic acid (SA)-modified selenium nanoparticles coated with a high blood-brain barrier permeability peptide-B6 peptide for potential use in Alzheimer's disease.

The blood-brain barrier (BBB) is a formidable gatekeeper toward exogenous substances, playing an important role in brain homeostasis and maintaining a healthy microenvironment for complex neuronal activities. However, it also greatly hinders drug permeability into the brain and limits the management of brain diseases. The development of new drugs that show improved transport across the BBB represents a promising strategy for Alzheimer's disease (AD) intervention. Whereas, previous study of receptor-mediated endogenous BBB transport systems has focused on a strategy of using transferrin to facilitate brain drug delivery system, a system that still suffers from limitations including synthesis procedure, stability and immunological response. In the present study, we synthetised sialic acid (SA)-modified selenium (Se) nanoparticles conjugated with an alternative peptide-B6 peptide (B6-SA-SeNPs, a synthetic selenoprotein analogue), which shows high permeability across the BBB and has the potential to serve as a novel nanomedicine for disease modification in AD. Laser-scanning confocal microscopy, flow cytometry analysis and inductively coupled plasma-atomic emission spectroscopy ICP-AES revealed high cellular uptake of B6-SA-SeNPs by cerebral endothelial cells (bEnd.3). The transport efficiency of B6-SA-SeNPs was evaluated in a Transwell experiment based on in vitro BBB model. It provided direct evidence for B6-SA-SeNPs crossing the BBB and being absorbed by PC12 cells. Moreover, inhibitory effects of B6-SA-SeNPs on amyloid-ß peptide (Aß) fibrillation could be demonstrated in PC12 cells and bEnd3 cells. B6-SA-SeNPs could not only effectively inhibit Aß aggregation but could disaggregate preformed Aß fibrils into non-toxic amorphous oligomers. These results suggested that B6-SA-SeNPs may provide a promising platform, particularly for the application of nanoparticles in the treatment of brain diseases. STATEMENT OF SIGNIFICANCE: Alzheimer's disease (AD) is the world's most common form of dementia characterized by intracellular neurofibrillary tangles in the brain. Over the past decades, the blood-brain barrier (BBB) limits access of therapeutic or diagnostic agents into the brain, which greatly hinders the development of new drugs for treating AD. In this work, we evaluated the efficiency of B6-SA-SeNPs across BBB and investigated the interactions between B6-SA-SeNPs and amyloid-ß peptide (Aß). We confirm that B6-SA-SeNPs could provide a promising platform because of its high brain delivery efficiency, anti-amyloid properties and anti-oxidant properties, which may serve as a novel nanomedicine for the application in the treatment of brain diseases.

PEG modified graphene oxide loaded with EALYLV peptides for inhibiting the aggregation of hIAPP associated with type-2 diabetes.

Human islet amyloid polypeptide (hIAPP) was found as amyloid aggregate deposits in the pancreatic islets of patients with type-2 diabetes and studies showed that insulin and its derivatives were the potent inhibitors of hIAPP aggregation. However, several emerging therapies with this goal showed limited success due to the instability and inefficiency of insulin derivatives. Nanosized graphene oxide (nGO) possesses high stability and affinity toward aromatic rings. In this study, an insulin-derived peptide, EALYLV, was stabilized by loading on nGO@PEG to inhibit aggregation and hIAPP-induced cytotoxicity. The results showed that nGO@PEG@EALYLV (abbreviated as nGO@PEG@E) can effectively inhibit the aggregation of hIAPP via electrostatic adsorption and specific binding to the active sites of hIAPP. We further evaluated the protective effect of nGO@PEG@E on INS-1 cells in the presence of hIAPP. Treatment with nGO@PEG@E could significantly elevate the viability of INS-1 cells, decrease the level of intracellular reactive oxygen species, and stabilize mitochondrial membrane potential. All the results indicated that nGO@PEG@E could inhibit the aggregation of hIAPP, which reduces its cytotoxicity.

Enantiomers of cysteine-modified SeNPs (d/lSeNPs) as inhibitors of metal-induced Aß aggregation in Alzheimer's disease.

Chiral molecules, which selectively target and inhibit amyloid ß-peptide (Aß) aggregation, have potential use as therapeutic agents for the treatment of Alzheimer's disease (AD). Here we use cysteine enantiomer-modified SeNPs (abbreviated as d/lSeNPs) to demonstrate that surface chirality strongly influences the formation of Aß aggregates in the presence of metal ions, such as Zn2+ or Cu2+. The two chiral molecule modified nanoparticles could inhibit the formation of Aß fibrils by binding Aß, thus blocking the formation of Aß fibrils and blocking the metal binding sites. Of the two enantiomers, d/SeNPs appear to more effectively inhibit Aß fibril formation due to a greater affinity for Aß than that of l/SeNPs. Additionally, d/lSeNPs appeared to reduce Aß and metal ion-induced neurotoxicity. Treatment with d/lSeNPs can also decrease the levels of intracellular reactive oxygen species, and stabilize the mitochondrial membrane potential. Of the two enantiomers, d/SeNPs were more effective in protecting the cells than l/SeNPs, and this could be due to d/SeNPs being selectively absorbed by PC12 cells, maintaining cellular redox potentials, and protecting cells against oxidative stress to a greater extent than l/SeNPs. From these results, it appears that chiral molecules can bring novel insight into better drug treatment designs for Alzheimer's disease.

Epigallocatechin-3-gallate (EGCG)-stabilized selenium nanoparticles coated with Tet-1 peptide to reduce amyloid-ß aggregation and cytotoxicity.

Alzheimer's disease (AD), the most common neurodegenerative disease, is caused by an accumulation of amyloid-ß (Aß) plaque deposits in the brains. Evidence is increasingly showing that epigallocatechin-3-gallate (EGCG) can partly protect cells from Aß-mediated neurotoxicity by inhibiting Aß aggregation. In order to better understand the process of Aß aggregation and amyloid fibril disaggregation and reduce the cytotoxicity of EGCG at high doses, we attached EGCG onto the surface of selenium nanoparticles (EGCG@Se). Given the low delivery efficiency of EGCG@Se to the targeted cells and the involvement of selenoprotein in antioxidation and neuroprotection, which are the key factors for preventing the onset and progression of AD, we synthesized EGCG-stabilized selenium nanoparticles coated with Tet-1 peptide (Tet-1-EGCG@Se, a synthetic selenoprotein analogue), considering the affinity of Tet-1 peptide to neurons. We revealed that Tet-1-EGCG@Se can effectively inhibit Aß fibrillation and disaggregate preformed Aß fibrils into nontoxic aggregates. In addition, we found that both EGCG@Se and Tet-1-EGCG@Se can label Aß fibrils with a high affinity, and Tet-1 peptides can significantly enhance the cellular uptake of Tet-1-EGCG@Se in PC12 cells rather than in NIH/3T3 cells.

HDAC inhibitors for the treatment of cancer.

Histone deacetylase (HDAC) inhibitors are a new class of cancer chemotherapeutics in clinical development that target the family of enzymes that catalyze the removal of the acetyl modification on lysine residues of proteins, including the core nucleosomal histones H2A, H2B, H3 and H4. The balance of nucleosomal histone acetylation is maintained through the opposing actions of histone acetyltransferases (HATs) and HDACs, and plays an important regulatory role in gene transcription. Alterations in both HATs and HDACs have been identified in tumor cells and may contribute to the altered gene expression found in many cancers. Inhibitors of HDAC activity induce cell cycle arrest, differentiation or apoptosis in tumor cells, and inhibit tumor growth in a variety of rodent models of cancer. Several structurally diverse HDAC inhibitors have entered clinical trials and are demonstrating encouraging antitumor activity in a variety of cancer types. As we learn more about these enzymes and the biological processes that they regulate, a strong rationale is emerging for the development of HDAC inhibitors as anticancer agents.

The histone deacetylase inhibitor SAHA arrests cancer cell growth, up-regulates thioredoxin-binding protein-2, and down-regulates thioredoxin.

Suberoylanilide hydroxamic acid (SAHA) is a potent inhibitor of histone deacetylases (HDACs) that causes growth arrest, differentiation, and/or apoptosis of many tumor types in vitro and in vivo. SAHA is in clinical trials for the treatment of cancer. HDAC inhibitors induce the expression of less than 2% of genes in cultured cells. In this study we show that SAHA induces the expression of vitamin D-up-regulated protein 1/thioredoxin-binding protein-2 (TBP-2) in transformed cells. As the expression of TBP-2 mRNA is increased, the expression of a second gene, thioredoxin, is decreased. In transient transfection assays, HDAC inhibitors induce TBP-2 promoter constructs, and this induction requires an NF-Y binding site. We report here that TBP-2 expression is reduced in human primary breast and colon tumors compared with adjacent tissue. These results support a model in which the expression of a subset of genes (i.e., including TBP-2) is repressed in transformed cells, leading to a block in differentiation, and culture of transformed cells with SAHA causes re-expression of these genes, leading to induction of growth arrest, differentiation, and/or apoptosis.