Beyond DNA binding - a review of the potential mechanisms mediating quinacrine's therapeutic activities in parasitic infections, inflammation, and cancers

This is an in-depth review of the history of quinacrine as well as its pharmacokinetic properties and established record of safety as an FDA-approved drug. The potential uses of quinacrine as an anti-cancer agent are discussed with particular attention to its actions on nuclear proteins, the arachidonic acid pathway, and multi-drug resistance, as well as its actions on signaling proteins in the cytoplasm. In particular, quinacrine's role on the NF-κB, p53, and AKT pathways are summarized

Depression in Men and Women One Year Following Traumatic Brain Injury (TBI): A TBI Model Systems Study

In the general population, females experience depression at significantly higher rates than males. Individuals with traumatic brain injury (TBI) are at substantially greater risk for depression compared to the overall population. Treatment of, and recovery from, TBI can be hindered by depression; comorbid TBI and depression can lead to adverse outcomes and negatively affect multiple aspects of individuals’ lives. Gender differences in depression following TBI are not well understood, and relevant empirical findings have been mixed. Utilizing the Patient Health Questionnaire-9 (PHQ-9) 1 year after TBI, we examined whether women would experience more severe depressive symptoms, and would endorse higher levels of depression within each category of depression severity, than would men. Interestingly, and contrary to our hypothesis, men and women reported mild depression at equal rates; PHQ-9 total scores were slightly lower in women than in men. Men and women did not differ significantly in any PHQ-9 depression severity category. Item analyses, yielded significant gender differences on the following items: greater concentration difficulties (cognitive problems) in men and more sleep disturbances (psychosomatic issues) in women per uncorrected two-sample Z-test for proportions analyses; however, these results were not significant after the family-wise Bonferroni correction. Our results indicate that, in contrast to the general population, mild depression in persons with moderate to severe TBI may not be gender-specific. These findings underscore the need for early identification, active screening, and depression treatment equally for men and women to improve emotional well-being, promote recovery, and enhance quality of life following TBI

Burden of Care Implications and Association of Intracranial Hypertension With Extremely Severe Post-traumatic Amnesia After Traumatic Brain Injury: A 5-Year Retrospective Longitudinal Study

Post-traumatic amnesia (PTA) is characterized by a state of disorientation and confusion following traumatic brain injury (TBI). Few studies have looked at the effect of prolonged PTA on the functional outcomes beyond 1 year post-injury. This study aims to evaluate the burden of care in individuals with extremely severe PTA (esPTA; PTA >28 days) from acute inpatient rehabilitation admission to 5 years post-injury as well as the association between intracranial hypertension (ICH; Intracranial pressure (ICP) ≥20 mmHg) and esPTA status. Three hundred and forty-two individuals with moderate to severe TBI enrolled in the Northern California TBI Model System (TBIMS) of Care were included in this study. The FIM® instrument was chosen as the outcome measurement as it is a widely used functional assessment in the rehabilitation community. Repeated measure ANOVA revealed greater burden of care based on FIM® total scores (p < 0.001) from admission to 5-year follow-up for the esPTA group compared to the non-esPTA group (PTA ≤ 28 days). Unlike the non-esPTA group where FIM® total score plateaued 1 year post-injury, FIM® total score continued to improve up to 2 years post-injury for the esPTA group. The odds of developing esPTA was ~3 times higher for individuals with ICH vs. individuals without ICH (p < 0.001). In conclusion, individuals with esPTA have increased short- and long-term burden of care and the presence of ICH during hospitalization increased the odds of experiencing esPTA. These results may help the rehabilitation team and family in planning care post rehabilitation discharge

Ten-year safety of pluripotent stem cell transplantation in acute thoracic spinal cord injury.

OBJECTIVE: The purpose of this study was to evaluate the safety of oligodendrocyte progenitor cells (LCTOPC1) derived from human pluripotent stem cells administered between 7 and 14 days postinjury to patients with T3 to T11 neurologically complete spinal cord injury (SCI). The rationale for this first-in-human trial was based on evidence that administration of LCTOPC1 supports survival and potential repair of key cellular components and architecture at the SCI site. METHODS: This study was a multisite, open-label, single-arm interventional clinical trial. Participants (n = 5) received a single intraparenchymal injection of 2 × 106 LCTOPC1 caudal to the epicenter of injury using a syringe positioning device. Immunosuppression with tacrolimus was administered for a total of 60 days. Participants were followed with annual in-person examinations and MRI for 5 years at the time of this report and will be followed with annual telephone questionnaires for 6 to 15 years postinjection. The primary endpoint was safety, as measured by the frequency and severity of adverse events related to the LCTOPC1 injection, the injection procedure, and/or the concomitant immunosuppression administered. The secondary endpoint was neurological function as measured by sensory scores and lower-extremity motor scores as measured by the International Standards for Neurological Classification of Spinal Cord Injury examinations. RESULTS: No unanticipated serious adverse events related to LCTOPC1 have been reported with 98% follow-up of participants (49 of 50 annual visits) through the first 10 years of the clinical trial. There was no evidence of neurological decline, enlarging masses, further spinal cord damage, or syrinx formation. MRI results during the long-term follow-up period in patients administered LCTOPC1 cells showed that 80% of patients demonstrated T2 signal changes consistent with the formation of a tissue matrix at the injury site. CONCLUSIONS: This study provides crucial first-in-human safety data supporting the pursuit of future human embryonic stem cell-derived therapies. While we cannot exclude the possibility of future adverse events, the experience in this trial provides evidence that this cell type can be well tolerated by patients, with an event-free period of up to 10 years. Based on the safety profile of LCTOPC1 obtained in this study, a cervical dose escalation trial was initiated (NCT02302157)

Molecular targets in head and neck cancer

EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Explicit vs. Contrastive-based Instruction of Formulaic Expressions in Developing EFL Learners’ Reading Ability

As an integrative component of textual structure, formulaic expressions (FEs) play a key role in communicating the message and comprehending the text. Furthermore, interlingually contrastive features of FEs add to their both significance and complexity of their instruction. Given these facts, this study was an attempt to explore a sound mechanism on how to teach FEs; whether an explicit or CA-based approach to FEs instruction could entail various achievements among EFL learners’ reading ability. To this end, three groups of Iranian EFL learners, identified as homogeneous based on Nelson Proficiency Test, were classified into one control and two experimental (i.e. explicit and CA-based instruction) ones. They were exposed to conventional, explicit and CA-based instructions of a set of selected FEs developed into and presented in the form of an instructional handout. Their Knowledge of reading was also tested based on a researcher-made diagnostic test prior to the experiment. Both quantitative and qualitative paradigms were employed to measure both the achievements and the extent of contrast between Persian and English languages in terms of FEs. The former analysis revealed significance difference among the groups in terms of instruction type effectiveness; both explicit and CA-based instruction groups outperformed the control group; on the contrary, no statistically significant difference was revealed between the experimental groups. Additionally, the latter paradigm revealed differences and mismatches between Persian and English FEs in terms of semantic, syntactic and pragmatic parameters. The findings could be insightful for EFL instructors, learners, textbook writers, and syllabus designers to take into account issues like these in their pedagogical programs