Active Targeting Gold Nanoparticle for Chemotherapy Drug Delivery: A Review

Objective Active targeting strategy in chemotherapy drug delivery aims to improve the therapeutic outcomes and minimise the side effects of chemotherapeutics. This review discusses utilising ligands attached to gold nanoparticles (AuNPs) along with several specific ligands attached to AuNPs for active targeting in chemotherapy drug delivery. Key finding Antibodies, peptides, vitamins, DNA, polysaccharides, aptamers, and hormones showed active-targeting abilities as ligands attached to AuNPs. Active-targeting AuNPs enhanced cellular uptake and cytotoxicity in a specific cancer cell in vitro while reducing tumor growth in vivo by improving the photothermal, photodynamic and chemotherapy effects. Active-targeting ligands increased the internalization of AuNPs loaded onto the specific tumour site and minimised the accumulation in the normal site. Conclusion AuNPs with active-targeting ligands such as antibodies, peptides, vitamins, DNA polysaccharides, aptamers, and hormones can improve the therapeutic outcomes of chemotherapeutics and can attenuate the toxicity effect in normal cells. For further research and development, researchers should be addressing AuNP characterization, drug–ligand disposition, active-targeting AuNP quantification, and target-AuNPs pertinence concerning the desired therapeutic outcomes.

Stochastic Epigenetic Mutations Influence Parkinson’s Disease Risk, Progression, and Mortality

Background: Stochastic epigenetic mutations (SEM) reflect a deviation from normal site-specific methylation patterns. Epigenetic mutation load (EML) captures the accumulation of SEMs across an individual’s genome and may reflect dysfunction of the epigenetic maintenance system in response to epigenetic challenges. Objective: We investigate whether EML is associated with PD risk and time to events (i.e., death and motor symptom decline). Methods: We employed logistic regression and Cox proportional hazards regression to assess the association between EML and several outcomes. Our analyses are based on 568 PD patients and 238 controls from the Parkinson’s disease, Environment and Genes (PEG) study, for whom blood-based methylation data was available. Results: We found an association for PD onset and EML in all genes (OR = 1.90; 95%CI 1.52-2.37) and PD-related genes (OR = 1.87; 95%CI 1.50-2.32). EML was also associated with time to a minimum score of 35 points on the motor UPDRS exam (OR = 1.28; 95%CI 1.06-1.56) and time to death (OR = 1.29, 95%CI 1.11-1.49). An analysis of PD related genes only revealed five intragenic hotspots of high SEM density associated with PD risk. Conclusion: Our findings suggest an enrichment of methylation dysregulation in PD patients in general and specifically in five PD related genes. EML may also be associated with time to death and motor symptom progression in PD patients.

Study of correlations between CT properties of retrieved cerebral thrombi with treatment outcome of stroke patients

Background All the patients with suspected stroke are directed to whole-brain CT scan. The purpose of this scan is to look for early features of ischemia and to rule out alternative diagnoses than stroke. In case of ischemic stroke, CT diagnostics (including CT angiography) is used mainly to locate the occlusion and its size, while the Hounsfield Units (HU) values of the thrombus causing the stroke are usually overlooked on CT scan or considered not important. The aim of this study was to demonstrate that the HU value is relevant and can help in better treatment planning. Patients and methods There were 25 patients included in the study, diagnosed with ischemic stroke in the middle cerebral artery (MCA) territory. In all patients, systemic thrombolysis was not successful and the mechanical recanalization was needed. The retrieved thrombi were also analyzed histologically for the determination of red blood cells (RBC) proportion. CT of the proximal MCA (M1) segment was analyzed for average HU value and its variability both in the occluded section and the symmetrical normal site. These CT parameters were then statistically studied for the possible correlations with different clinical, histological and procedure parameters using the Linear Regression and the Pearson correlation coefficient. Results Relevant positive correlations were found between average HU value of thrombus and outcome modified Rankin Scale (mRS), initial mRS, number of passes with thrombectomy device as well as RBC proportion. Conclusions Results of the present study suggest that measured HU values in CT images of the cerebral thrombi may help in the assessment of thrombus compaction and therefore better treatment planning.

The mitochondrial intermembrane space: the most constricted mitochondrial sub-compartment with the largest variety of protein import pathways

The mitochondrial intermembrane space (IMS) is the most constricted sub-mitochondrial compartment, housing only about 5% of the mitochondrial proteome, and yet is endowed with the largest variability of protein import mechanisms. In this review, we summarize our current knowledge of the major IMS import pathway based on the oxidative protein folding pathway and discuss the stunning variability of other IMS protein import pathways. As IMS-localized proteins only have to cross the outer mitochondrial membrane, they do not require energy sources like ATP hydrolysis in the mitochondrial matrix or the inner membrane electrochemical potential which are critical for import into the matrix or insertion into the inner membrane. We also explore several atypical IMS import pathways that are still not very well understood and are guided by poorly defined or completely unknown targeting peptides. Importantly, many of the IMS proteins are linked to several human diseases, and it is therefore crucial to understand how they reach their normal site of function in the IMS. In the final part of this review, we discuss current understanding of how such IMS protein underpin a large spectrum of human disorders.

Distal Migration and Ectopic Eruption of the Mandibular First Premolar: Case Report

Migration describes the movement of an unerupted tooth within the bone when normal eruption is prevented and the tooth leaves its normal site of development. This report describes a case of distal migration and ectopic eruption of the mandibular first premolar in an 8.5-year-old boy. Following early extraction of the primary second molar, the first premolar migrated distally through the extraction site of the primary second molar and erupted into occlusion just mesial of the permanent first molar.

Distal Migration and Ectopic Eruption of the Mandibular First Premolar: A Case Report

Migration describes the movement of an unerupted tooth within the bone when normal eruption is prevented and the tooth leaves its normal site of development. This report describes a case of distal migration and ectopic eruption of the mandibular first premolar in an 8.5-year-old boy. Following early extraction of the primary second molar, the first premolar migrated distally through the extraction site of the primary second molar and erupted into occlusion just mesial of the permanent first molar.

Putative pore-forming subunits of the mechano-electrical transduction channel, Tmc1/2b, require Tmie to localize to the site of mechanotransduction in zebrafish sensory hair cells

Mutations in transmembrane inner ear (TMIE) cause deafness in humans; previous studies suggest involvement in the mechano-electrical transduction (MET) complex in sensory hair cells, but TMIE’s precise role is unclear. In tmie zebrafish mutants, we observed that GFP-tagged Tmc1 and Tmc2b, which are putative subunits of the MET channel, fail to target to the hair bundle. In contrast, overexpression of Tmie strongly enhances the targeting of Tmc2b-GFP to stereocilia. To identify the motifs of Tmie underlying the regulation of the Tmcs, we systematically deleted or replaced peptide segments. We then assessed localization and functional rescue of each mutated/chimeric form of Tmie in tmie mutants. We determined that the first putative helix was dispensable and identified a novel critical region of Tmie, the extracellular region and transmembrane domain, which mediates both mechanosensitivity and Tmc2b-GFP expression in bundles. Collectively, our results suggest that Tmie’s role in sensory hair cells is to target and stabilize Tmc subunits to the site of MET.Author summaryHair cells mediate hearing and balance through the activity of a pore-forming channel in the cell membrane. The transmembrane inner ear (TMIE) protein is an essential component of the protein complex that gates this so-called mechanotransduction channel. While it is known that loss of TMIE results in deafness, the function of TMIE within the complex is unclear. Using zebrafish as a deafness model, Pacentine and Nicolson demonstrate that Tmie is required for the localization of other essential complex members, the transmembrane channel-like (Tmc) proteins, Tmc1/2b. They then evaluate twelve unique versions of Tmie, each containing mutations to different domains of Tmie. This analysis reveals that some mutations in Tmie cause dysfunctional gating of the channel as demonstrated through reduced hair cell activity, and that these same dysfunctional versions also display reduced Tmc expression at the normal site of the channel. These findings link hair cell activity with the levels of Tmc in the bundle, reinforcing the currently-debated notion that the Tmcs are the pore-forming subunits of the mechanotransduction channel. The authors conclude that Tmie, through distinct regions, is involved in both trafficking and stabilizing the Tmcs at the site of mechanotransduction.

A case of a cervico-isthmic pregnancy without abnormal location of placenta

Cervico-isthmic pregnancies (CIP) are often complicated by massive hemorrhage due to placenta previa and adhesion. Herein, we present a case of CIP without placenta previa, complicated by cervical incompetency. A 39-year-old multiparous woman was diagnosed with CIP at 8 weeks. The placenta was located on the normal site, and no significant ultrasonographic findings were noted after 14 weeks. At 20 weeks, a cervical incompetency was complicated. A healthy infant was delivered by a cesarean hysterectomy at term. Histopathological examination confirmed CIP with placenta increta. In cases with CIP without placenta previa, the diagnosis during early gestation and careful evaluation of uterine cervix is essential to avoid severe complications.