\u3cem\u3eO\u27Keeffe v. Ireland\u3c/em\u3e: The State\u27s Obligation to Protect Children from Sexual Assault in State Schools

Ireland’s unique primary education system creates a national school system that is denominational, yet state-financed. The Irish government defers managerial duties to the Catholic Church, and this deference of duties relieves Ireland from liability. As a result, students in Ireland attending primary schools historically were not guaranteed legal protection from sexual assaults committed by faculty members. On January 28, 2014, the Grand Chamber of the European Court of Human Rights held in O’Keeffe v. Ireland that despite Ireland’s delegation of authority to religious denominations, the State was obligated to protect students from sexual assaults. The court reasoned that the State had an obligation to guarantee Article 3 fundamental rights, because no one, especially vulnerable children in primary education, should be subject to inhuman treatment. The court also noted that such an obligation could not be absolved through the delegation of powers. This Comment examines the court’s reasoning and argues that its decision leaves unanswered the scope of interpretation in future cases of abuse

Trans-Differentiation of Neural Stem Cells: A Therapeutic Mechanism Against the Radiation Induced Brain Damage

Radiation therapy is an indispensable therapeutic modality for various brain diseases. Though endogenous neural stem cells (NSCs) would provide regenerative potential, many patients nevertheless suffer from radiation-induced brain damage. Accordingly, we tested beneficial effects of exogenous NSC supplementation using in vivo mouse models that received whole brain irradiation. Systemic supplementation of primarily cultured mouse fetal NSCs inhibited radiation-induced brain atrophy and thereby preserved brain functions such as short-term memory. Transplanted NSCs migrated to the irradiated brain and differentiated into neurons, astrocytes, or oligodendrocytes. In addition, neurotrophic factors such as NGF were significantly increased in the brain by NSCs, indicating that both paracrine and replacement effects could be the therapeutic mechanisms of NSCs. Interestingly, NSCs also differentiated into brain endothelial cells, which was accompanied by the restoration the cerebral blood flow that was reduced from the irradiation. Inhibition of the VEGF signaling reduced the migration and trans-differentiation of NSCs. Therefore, trans-differentiation of NSCs into brain endothelial cells by the VEGF signaling and the consequential restoration of the cerebral blood flow would also be one of the therapeutic mechanisms of NSCs. In summary, our data demonstrate that exogenous NSC supplementation could prevent radiation-induced functional loss of the brain. Therefore, successful combination of brain radiation therapy and NSC supplementation would provide a highly promising therapeutic option for patients with various brain diseases

Patient-Specific Orthotopic Glioblastoma Xenograft Models Recapitulate the Histopathology and Biology of Human Glioblastomas In Situ

SummaryFrequent discrepancies between preclinical and clinical results of anticancer agents demand a reliable translational platform that can precisely recapitulate the biology of human cancers. Another critical unmet need is the ability to predict therapeutic responses for individual patients. Toward this goal, we have established a library of orthotopic glioblastoma (GBM) xenograft models using surgical samples of GBM patients. These patient-specific GBM xenograft tumors recapitulate histopathological properties and maintain genomic characteristics of parental GBMs in situ. Furthermore, in vivo irradiation, chemotherapy, and targeted therapy of these xenograft tumors mimic the treatment response of parental GBMs. We also found that establishment of orthotopic xenograft models portends poor prognosis of GBM patients and identified the gene signatures and pathways signatures associated with the clinical aggressiveness of GBMs. Together, the patient-specific orthotopic GBM xenograft library represent the preclinically and clinically valuable “patient tumor’s phenocopy” that represents molecular and functional heterogeneity of GBMs

Helicity-driven chiral self-sorting supramolecular polymerization with Ag+: right- and left-helical aggregates

The study of chiral self-sorting is extremely important for understanding biological systems and for developing applications for the biomedical field. In this study, we attempted unprecedented chiral self-sorting supramolecular polymerization accompanying helical inversion with Ag+ in one enantiomeric component. Bola-type terpyridine-based ligands (R-L-1 and S-L-1) comprising R- or S-alanine analogs were synthesized. First, R-L-1 dissolved in DMSO/H2O (1 : 1, v/v) forms right-handed helical fibers (aggregate I) via supramolecular polymerization. However, after the addition of AgNO3 (0.2-1.1 equiv.) to the R-L-1 ligand, in particular, it was found that aggregate II with left-handed helicity is generated from the [R-L-1(AgNO3)(2)] complex through the [R-(LAg)-Ag-1](+) complex via the dissociation of aggregate I by a multistep with an off pathway, thus demonstrating interesting self-sorting properties driven by helicity and shape discrimination. In addition, the [R-L-1(AgNO3)(2)] complex, which acted as a building block to generate aggregate III with a spherical structure, existed as a metastable product during the formation of aggregate II in the presence of 1.2-1.5 equiv. of AgNO3. Furthermore, the AFM and CD results of two samples prepared using aggregates I and III with different volume ratios were similar to those obtained upon the addition of AgNO3 to free R-L-1. These findings suggest that homochiral self-sorting in a mixture system occurred by the generation of aggregate II composed of the [R-(LAg)-Ag-1](+) complex via the rearrangement of both, aggregates I and III. This is a unique example of helicity- and shape-driven chiral self-sorting supramolecular polymerization induced by Ag+ starting from one enantiomeric component. This research will improve understanding of homochirality in complex biological models and contribute to the development of new chiral materials and catalysts for asymmetric synthesis

Multiple Endocrine Neoplasia Type 1 with Multiple Leiomyomas Linked to a Novel Mutation in the MEN1 Gene

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominantly inherited syndrome. MEN1 is characterized by the presence of functioning and nonfunctioning tumors or hyperplasia of the pituitary gland, parathyroid glands, and pancreatic islet cells. In addition, MEN1 carriers can have adrenal or thyroid tumors and non-endocrine tumors, such as lipomas, angiofibromas, and leiomyomas. Although leiomyoma is not a major component of MEN1, it is thought to occur more frequently than expected. However, there has been no report of a case of MEN1 with leiomyoma in Korea so far. This report describes a patient with multiple leiomyomas in MEN1. A 50-year-old woman was referred for further evaluation of elevated calcium levels and osteoporosis. Biochemical abnormalities included hypercalcemia with elevated parathyroid hormone. There was hyperprolactinemia with pituitary microadenoma in sella MRI. An abdominal MRI demonstrated adrenal nodules and leiomyomas in the bladder and uterus. Endoscopic ultrasonography demonstrated esophageal leiomyoma and pancreatic islet cell tumor. A subtotal parathyroidectomy with thymectomy was performed. Sequencing of the MEN1 gene in this patient revealed a novel missense mutation (D350V, exon 7). This is the first case of MEN1 accompanied with multiple leiomyomas, parathyroid adenoma, pituitary adenoma, pancreatic tumor, and adrenal tumor

Factors Associated with HIV-1 Proviral DNA Loads in Patients with Undetectable Plasma RNA Load

To evaluate factors associated with human immunodeficiency virus type 1 (HIV-1) proviral DNA load, we conducted a cross-sectional study of 36 chronically HIV-1-infected individuals with undetectable plasma viral RNA. We used real-time polymerase chain reaction to determine the number of HIV-1 proviral DNA copies per 106 peripheral blood mononuclear cells. The mean level of plasma viral RNA when the CD4+ T cell count was above 500 cells/µL without highly active antiretroviral therapy (HAART) was significantly associated with proviral DNA load at the time of undetectable plasma HIV RNA with HAART. Strategies to reduce the level of plasma viral RNA when patients' CD4+ T cell counts are above 500 cells/µL without HAART could help reduce HIV-1 proviral DNA load

A phase IA dose-escalation study of PHI-101, a new checkpoint kinase 2 inhibitor, for platinum-resistant recurrent ovarian cancer

Abstract Background PHI-101 is an orally available, selective checkpoint kinase 2 (Chk2) inhibitor. PHI-101 has shown anti-tumour activity in ovarian cancer cell lines and impaired DNA repair pathways in preclinical experiments. Furthermore, the in vivo study suggests the synergistic effect of PHI-101 through combination with PARP inhibitors for ovarian cancer treatment. The primary objective of this study is to evaluate the safety and tolerability of PHI-101 in platinum-resistant recurrent ovarian cancer. Methods Chk2 inhibitor for Recurrent EpitheliAl periToneal, fallopIan, or oVarian cancEr (CREATIVE) trial is a prospective, multi-centre, phase IA dose-escalation study. Six cohorts of dose levels are planned, and six to 36 patients are expected to be enrolled in this trial. Major inclusion criteria include ≥ 19 years with histologically confirmed epithelial ovarian cancer, fallopian tube carcinoma, or primary peritoneal cancer. Also, patients who showed disease progression during platinum-based chemotherapy or disease progression within 24 weeks from completion of platinum-based chemotherapy will be included, and prior chemotherapy lines of more than five will be excluded. The primary endpoint of this study is to determine the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of PHI-101. Discussion PHI-101 is the first orally available Chk2 inhibitor, expected to show effectiveness in treating recurrent ovarian cancer. Through this CREATIVE trial, DLT and MTD of this new targeted therapy can be confirmed to find the recommended dose for the phase II clinical trial. This study may contribute to developing a new combination regimen for the treatment of ovarian cancer. Trial registration ClinicalTrials.gov Identifier: NCT04678102

Emission Characteristics of Hazardous Air Pollutants from Medium-Duty Diesel Trucks Based on Driving Cycles

Studies on the characteristics of hazardous air pollutants (HAPs) in the emissions of medium-duty diesel trucks are significantly insufficient compared to those on heavy-duty trucks. This study investigated the characteristics of regulated pollutants and HAPs, such as volatile organic compounds (VOCs), aldehydes, and polycyclic aromatic hydrocarbons (PAHs), and estimated non-methane hydrocarbon (NMHC) speciation in the emissions of medium-duty diesel trucks. Ten medium-duty diesel trucks conforming to Euros 5 and 6 were tested for four various driving cycles (WLTC, NEDC, CVS-75, and NIER-9) using a chassis dynamometer. In an urban area such as Seoul, CO and NMHC emissions were increased because of its longer low-speed driving time. NOx emissions were the highest in the high-speed phase owing to the influence of thermal NOx. PM emissions were almost not emitted because of the DPF installation. Alkanes dominated non-methane volatile organic compound (NMVOC) emissions, 36–63% of which resulted from the low reaction of the diesel oxidation catalyst. Formaldehyde emissions were the highest for 35–53% among aldehydes irrespective of driving cycles. By sampling the particle-phase of PAHs, we detected benzo(k)fluoranthene and benzo(a)pyrene and estimated the concentrations of the gas-phase PAHs with models to obtain the total PAH concentrations. In the particle portion, benzo(k)fluoranthene and benzo(a)pyrene were over 69% and over 91%, respectively. The toxic equivalency quantities of benzo(k)fluoranthene and benzo(a)pyrene from NIER-9 (cold) for both Euro 5 and Euro 6 vehicles were more than five times higher than those of NIER (hot) and NEDC. In the case of NMHC speciation, formaldehyde emissions were the highest for 10–45% in all the driving cycles. Formaldehyde and benzene must be controlled in the emissions of medium-duty diesel trucks to reduce their health threats. The results of this study will aid in establishing a national emission inventory system for HAPs of mobile sources in Korea