Identification of the Variations in the CPT1B and CHKB Genes Along with the HLA-DQB1*06:02 Allele in Turkish Narcolepsy Patients and Healthy Persons

The pretrial process of discovery governed by Federal and Maine Rule of Civil Procedure 26 enables plaintiffs in product liability actions to delve where few people have delved before—into a corporation\u27s internal memoranda, competitive practices, and secret product or design information as well as other less sensitive information in a company\u27s possession. Discovery, in this context as in others, is a powerful tool determined by the courts to be necessary for the just litigation of claims. As a balance to the leeway given parties to compel production of information in discovery, federal and Maine courts have the authority under Federal and Maine Rule 26(c) to protect parties and witnesses from the harm that can result from a disclosure of confidential information. The court may enter a protective order, sometimes called a confidentiality order, restricting a party receiving the information from disseminating it or from making any use of the information other than for purposes of the specific litigation. In addition, public access to information after its use in the litigation often is barred by such orders. Irrespective of the legal interests of the parties involved in the case, however, the public outside the legal community may have an interest in the information, and the receiving party may wish to disclose it. This point is brought into focus by the occasional case in which confidential information raises dramatic health issues, such as the recent reports of potential health risks from silicone breast implants. Judicial use of Rule 26(c) to restrict dissemination of discovered information predictably has invited First Amendment claims of free speech. Maine courts are empowered and exhorted by Maine Rule 26(c) to issue protective orders. Unlike the Federal Rule, Maine Rule 26(c) includes an admonition for the courts to exercise their powers to grant a protective order and other controls over discovery “with liberality . . . to protect parties and witnesses.” Whether conscious of the admonition or not, state courts in product liability cases have issued broadly constructed protective orders restricting plaintiffs, their attorneys and their witnesses from revealing information. The risk for all trial courts, confronted with the potential magnitude of discovery problems and hesitant to spend their limited time on this one procedural issue, is that the power to grant protective orders will degenerate into a perfunctory granting of most or even all such requests. The decision to grant such an order becomes perfunctory when the court does so without an appropriate “good cause” determination and without a careful fashioning of the order to minimize its impact on the affected parties. In Maine\u27s courts, despite the admonition to use the protective-order power liberally, the same considerations apply as fully as in federal courts to a determination of whether a protective order is justified. This Comment examines these considerations and concludes that trial courts must guard against exercising too freely their power to issue protective orders. Such an overly broad exercise of the power relieves movants of their burden to articulate with some specificity the potential harm constituting good cause for restricting parties\u27 and witnesses\u27 First Amendment interests. An understanding of the implications of protective orders should encourage courts to fashion such orders in a way that minimizes the effect on the parties and witnesses without sacrificing the protective purpose of the order

The importance of preoperative planning to perform safely temporal lobe surgery

Neurosurgeons should know the anatomy required for safe temporal lobe surgery approaches. The pre-sent study aimed to determine the angles and distances necessary to reach the temporal stem and tem-poral horn in surgical approaches for safe temporal lobe surgery by using a 3.0 T magnetic resonance imaging technique in post-mortem human brain hemispheres fixed by the Klingler method. In our study, 10 post-mortem human brain hemisphere specimens were fixed according to the Klingler method. Magnetic resonance images were obtained using a 3.0 T magnetic resonance imaging scanner after fixa-tion. Surgical measurements were conducted for the temporal stem and temporal horn by magnetic res-onance imaging, and dissection was then performed under a surgical microscope for the temporal stem. Each stage of dissection was achieved in high-quality three-dimensional images. The angles and distances to reach the temporal stem and temporal horn were measured in transcortical T1, trans-sulcal T1-2, transcortical T2, trans-sulcal T2-3, transcortical T3, and subtemporal trans-collateral sulcus approaches. The safe maximum posterior entry point for anterior temporal lobectomy was measured as 47.16 +/- 5.0 0 mm. Major white-matter fibers in this region and their relations with each other are shown. The dis-tances to the temporal stem and temporal horn, which are important in temporal lobe surgical interven-tions, were measured radiologically, and safe borders were determined. Surgical strategy and preoperative planning should consider the relationship of the lesion and white-matter pathways. (c) 2021 Elsevier Ltd. All rights reserved

Systematic characterization of chromatin modifying enzymes identifies KDM3B as a critical regulator in castration resistant prostate cancer

Androgen deprivation therapy (ADT) is the standard care for prostate cancer (PCa) patients who fail surgery or radiotherapy. While initially effective, the cancer almost always recurs as a more aggressive castration resistant prostate cancer (CRPC). Previous studies have demonstrated that chromatin modifying enzymes can play a critical role in the conversion to CRPC. However, only a handful of these potential pharmacological targets have been tested. Therefore, in this study, we conducted a focused shRNA screen of chromatin modifying enzymes previously shown to be involved in cellular differentiation. We found that altering the balance between histone methylation and demethylation impacted growth and proliferation. Of all genes tested, KDM3B, a histone H3K9 demethylase, was found to have the most antiproliferative effect. These results were phenocopied with a KDM3B CRISPR/Cas9 knockout. When tested in several PCa cell lines, the decrease in proliferation was remarkably specific to androgen-independent cells. Genetic rescue experiments showed that only the enzymatically active KDM3B could recover the phenotype. Surprisingly, despite the decreased proliferation of androgen-independent cell no alterations in the cell cycle distribution were observed following KDM3B knockdown. Whole transcriptome analyses revealed changes in the gene expression profile following loss of KDM3B, including downregulation of metabolic enzymes such as ARG2 and RDH11. Metabolomic analysis of KDM3B knockout showed a decrease in several critical amino acids. Overall, our work reveals, for the first time, the specificity and the dependence of KDM3B in CRPC proliferation

Parameters Influencing Gene Delivery Efficiency of PEGylated Chitosan Nanoparticles: Experimental and Modeling Approach

Experimentation of nanomedicine is labor-intensive, time-consuming, and requires costly laboratory consumables. Constructing a reliable mathematical model for such systems is also challenging due to the difficulties in gathering a sufficient number of data points. Artificial neural networks (ANNs) are indicated as an efficient approach in nanomedicine to investigate the cause-effect relationships and predict output variables. Herein, an ANN is adapted into plasmid DNA (pDNA) encapsulated and PEGylated chitosan nanoparticles cross-linked with sodium tripolyphosphate (TPP) to investigate the effects of critical parameters on the transfection efficiencies of nanoparticles. The ANN model is developed based on experimental results with three independent input variables: 1) polyethylene glycol (PEG) molecular weight, 2) PEG concentration, and 3) nanoparticle concentration, along with one output variable as a percentage of green fluorescent protein (GFP) expression, which refers to transfection efficiency. The constructed model is further validated with the leave-p-out cross-validation method. The results indicate that the developed model has good prediction capability and is influential in capturing the transfection efficiencies of different nanoparticle groups. Overall, this study reveals that the ANN could be an efficient tool for nanoparticle-mediated gene delivery systems to investigate the impacts of critical parameters in detail with reduced experimental effort and cost.ISSN:2699-930

Identification of SERPINE1 as a Regulator of Glioblastoma Cell Dispersal with Transcriptome Profiling

High mortality rates of glioblastoma (GBM) patients are partly attributed to the invasive behavior of tumor cells that exhibit extensive infiltration into adjacent brain tissue, leading to rapid, inevitable, and therapy-resistant recurrence. In this study, we analyzed transcriptome of motile (dispersive) and non-motile (core) GBM cells using an in vitro spheroid dispersal model and identified SERPINE1 as a modulator of GBM cell dispersal. Genetic or pharmacological inhibition of SERPINE1 reduced spheroid dispersal and cell adhesion by regulating cell-substrate adhesion. We examined TGFβ as a potential upstream regulator of SERPINE1 expression. We also assessed the significance of SERPINE1 in GBM growth and invasion using TCGA glioma datasets and a patient-derived orthotopic GBM model. SERPINE1 expression was associated with poor prognosis and mesenchymal GBM in patients. SERPINE1 knock-down in primary GBM cells suppressed tumor growth and invasiveness in the brain. Together, our results indicate that SERPINE1 is a key player in GBM dispersal and provide insights for future anti-invasive therapy design