Modulation of Tumor Tolerance in Primary Central Nervous System Malignancies

Central nervous system tumors take advantage of the unique immunology of the CNS and develop exquisitely complex stromal networks that promote growth despite the presence of antigen-presenting cells and tumor-infiltrating lymphocytes. It is precisely this immunological paradox that is essential to the survival of the tumor. We review the evidence for functional CNS immune privilege and the impact it has on tumor tolerance. In this paper, we place an emphasis on the role of tumor-infiltrating myeloid cells in maintaining stromal and vascular quiescence, and we underscore the importance of indoleamine 2,3-dioxygenase activity as a myeloid-driven tumor tolerance mechanism. Much remains to be discovered regarding the tolerogenic mechanisms by which CNS tumors avoid immune clearance. Thus, it is an open question whether tumor tolerance in the brain is fundamentally different from that of peripheral sites of tumorigenesis or whether it simply stands as a particularly strong example of such tolerance

Challenges Associated with Tyrosine Kinase Inhibitor Therapy for Metastatic Thyroid Cancer

Tyrosine kinase inhibitors (TKIs) which target angiogenesis are promising treatments for patients with metastatic medullary and differentiated thyroid cancers. Sorafenib, sunitinib, and pazopanib are commercially available drugs which have been studied in these diseases. Vandetanib is the first drug approved in the United States for treatment of medullary thyroid cancer. These TKIs are used as chronic therapies, and therefore it is imperative to understand the adverse event profile in order to avoid excessive toxicity and maintain patients on therapy as long as it proves beneficial. Here we review common toxicities, management of these, and other challenging situations that arise when using TKIs in patients with thyroid cancer

Selective migration of neuralized embryonic stem cells to stem cell factor and media conditioned by glioma cell lines

BACKGROUND: Pluripotent mouse embryonic stem (ES) cells can be induced in vitro to become neural progenitors. Upon transplantation, neural progenitors migrate toward areas of damage and inflammation in the CNS. We tested whether undifferentiated and neuralized mouse ES cells migrate toward media conditioned by glioma cell lines (C6, U87 & N1321) or Stem Cell Factor (SCF). RESULTS: Cell migration assays revealed selective migration by neuralized ES cells to conditioned media as well as to synthetic SCF. Migration of undifferentiated ES cells was extensive, but not significantly different from that of controls (Unconditioned Medium). RT-PCR analysis revealed that all the three tumor cell lines tested synthesized SCF and that both undifferentiated and neuralized ES cells expressed c-kit, the receptor for SCF. CONCLUSION: Our results demonstrate that undifferentiated ES cells are highly mobile and that neural progenitors derived from ES cells are selectively attracted toward factors produced by gliomas. Given that the glioma cell lines synthesize SCF, SCF may be one of several factors that contribute to the selective migration observed

Investigating the Causal Mechanisms of Symptom Recovery in Chronic Whiplash-associated Disorders Using Bayesian Networks

Objectives: The present study’s objective was to understand the causal mechanisms underpinning the recovery of individuals with whiplash-associated disorders (WAD). We applied Bayesian Networks (BN) to answer 2 study aims: (1) to identify the causal mechanism(s) of recovery underpinning neck-specific exercise (NSE), and (2) quantify if the cyclical pathway of the fear-avoidance model (FAM) is supported by the present data. Materials and Methods: We analyzed a prospective cohort data set of 216 individuals with chronic WAD. Fifteen variables were used to build a BN model: treatment group (NSE with or without a behavioral approach, or general physical activity), muscle endurance, range of motion, hand strength, neck proprioception, pain catastrophizing, fear, anxiety, depression, self-efficacy, perceived work ability, disability, pain intensity, sex, and follow-up time. Results: The BN model showed that neck pain reduction rate was greater after NSE compared with physical activity prescription (β=0.59 points per month [P<0.001]) only in the presence of 2 mediators: global neck muscle endurance and perceived work ability. We also found the following pathway of variables that constituted the FAM: anxiety, followed by depressive symptoms, fear, catastrophizing, self-efficacy, and consequently pain. Conclusions: e uncovered 2 mediators that explained the mechanisms of effect behind NSE, and proposed an alternative FAM pathway. The present study is the first to apply BN modelling to understand the causal mechanisms of recovery in WAD. In doing so, it is anticipated that such analytical methods could increase the precision of treatment of individuals with chronic WAD

Teaching Math with Confidence-Recommendations for Improving Numeracy from the Lens of Confidence Building

Despite the vast amount of literature surrounding the topic of financial literacy and related problems, there is still no universally accepted solution to this issue because the main factors causing financial literacy problems are still not fully understood both by researchers and current policy-makers. A possible new approach was discovered by Skagerlund et al. (2018), as their research suggested that financial literacy is driven by numeracy (the ability to process and perform basic numerical concepts and calculations) rather than direct knowledge about financial concepts. Given that numeracy is an effort based task, this policy brief provides a list of recommendations for developing numeracy from the standpoint of motivating effort to practice and improve the numeracy and mathematical skills of people for them to have the tools necessary to become financially literate, which may be more effective than creating a dedicated course on the topic of financial literacy. The results of the study confirmed that effort is indeed motivated by higher levels of confidence. Furthermore, information, particularly feedback regarding performance, plays a crucial role in shaping future confidence and, by extension, future levels of motivation and effort. Guided by these findings, this brief proposes the following policy recommendations

Testing the Relationship Between Confidence and Effort: A Behavioral Finance Perspective on the Problem of Financial Literacy

This experimental study tested the relationship between confidence and effort with the ultimate objective of discovering how these factors may influence financial literacy. This was done through a modified version of a slider test and ball allocation task. The population consisted of 85 random participants who were primarily approached through social media. A simple OLS regression, along with robustness checks, namely the Tobit model and instrumental variable (IV) regression model using Tobit estimators, were utilized to confirm the causal relationship between confidence and effort

Evaluating an online well-being program for college students during the COVID-19 pandemic

Introduction: The global COVID-19 pandemic has aggravated challenges involving college students’ mental health and well-being. Some literature suggested developing online programs to address the pandemic’s impact on college students’ mental health and well-being. Thus, this study assessed if significant improvement in well-being among college students can be observed after introducing an online well-being program.Methods: The study utilized a quantitative methodology, mainly using a two-group pretest-posttest design on 178 college students in a private college and state university. The experimental group received 3 months of the well-being program while the control resumed their activities of daily living (ADL). The modified positive emotion, engagement, relationship, meaning, and accomplishment (PERMA) profiler questionnaire was the primary evaluation instrument that measured the participants’ well-being. The first phase gathered the participants’ relevant profile and background, and the last phase concluded with the evaluation of the program. Data were analyzed using SPSS v.21.Results: Based on the post-evaluation PERMA scores, the experimental participants (M = 7.21, SD 1.70) did not differ much from the control (M = 7.07, SD = 1.55) according to a t-test t(176) = –1.07, p = 0.57 as computed using a two-sample independent t-test at a significance level of α = 0.05. The overall PERMA score description is normal functioning. The Pearson correlation of the experimental group’s pre-test and post-test scores (r(91) = 0.01, p = 0.904) and the control (r(83) = 0.04, p = 0.732) group did not indicate an evidence of a significant relationship.Conclusion: The results do not provide evidence of a significant difference and relationship between the experimental participants’ pre-test and post-test PERMA scores after the online well-being program

CSP alpha reduces aggregates and rescues striatal dopamine release in alpha-synuclein transgenic mice

alpha-Synuclein aggregation at the synapse is an early event in Parkinson's disease and is associated with impaired striatal synaptic function and dopaminergic neuronal death. The cysteine string protein (CSP alpha) and alpha-synuclein have partially overlapping roles in maintaining synaptic function and mutations in each cause neurodegenerative diseases. CSP alpha is a member of the DNAJ/HSP40 family of co-chaperones and like alpha-synuclein, chaperones the SNARE complex assembly and controls neurotransmitter release. alpha-Synuclein can rescue neurodegeneration in CSP alpha KO mice. However, whether alpha-synuclein aggregation alters CSP alpha expression and function is unknown. Here we show that alpha-synuclein aggregation at the synapse is associated with a decrease in synaptic CSP alpha and a reduction in the complexes that CSP alpha forms with HSC70 and STG alpha. We further show that viral delivery of CSP alpha rescues in uitro the impaired vesicle recycling in PC12 cells with alpha-synuclein aggregates and in uiuo reduces synaptic alpha-synuclein aggregates increasing monomeric alpha-synuclein and restoring normal dopamine release in 1-120h alpha Syn mice. These novel findings reveal a mechanism by which alpha-synuclein aggregation alters CSP alpha at the synapse, and show that CSP alpha rescues alpha-synuclein aggregation-related phenotype in 1-120h alpha Syn mice similar to the effect of alpha-synuclein in CSP alpha KO mice. These results implicate CSP alpha as a potential therapeutic target for the treatment of earlystage Parkinson's disease

Perineuronal net digestion with chondroitinase restores memory in mice with tau pathology.

Alzheimer's disease is the most prevalent tauopathy and cause of dementia. We investigate the hypothesis that reactivation of plasticity can restore function in the presence of neuronal damage resulting from tauopathy. We investigated two models with tau hyperphosphorylation, aggregation and neurodegeneration: a transgenic mouse model in which the mutant P301S tau is expressed in neurons (Tg P301S), and a model in which an adeno-associated virus expressing P301S tau (AAV-P301S) was injected in the perirhinal cortex, a region critical for object recognition (OR) memory. Both models show profound loss of OR memory despite only 15% neuronal loss in the Tg P301S and 26% in AAV-P301S-injected mice. Recordings from perirhinal cortex slices of 3month-old P301S transgenic mice showed a diminution in synaptic transmission following temporal stimulation. Chondroitinase ABC (ChABC) can reactivate plasticity and affect memory through actions on perineuronal nets. ChABC was injected into the perirhinal cortex and animals were tested for OR memory 1week later, demonstrating restoration of OR memory to normal levels. Synaptic transmission indicated by fEPSP amplitude was restored to control levels following ChABC treatment. ChABC did not affect the progression of neurodegenerative tauopathy. These findings suggest that increasing plasticity by manipulation of perineuronal nets offers a novel therapeutic approach to the treatment of memory loss in neurodegenerative disorders.This work was supported by the European Union Framework 7 Project Plasticise (S.Y., M.C., M.G.S., J.W.F., P.R., P.A., B.L.S.), the Wellcome Trust (L.M.S., T.J.B.), the Alzheimer's Research UK (M.G.S.), and the UK Medical Research Council (L.M.S., T.J.B.). J.W.F.'s work is supported by the ERC-ECMneuro, the Christopher and Dana Reeve Foundation and the NIHR Cambridge biomedical research center.This article was originally published in Experimental Neurology (S Yang, M Cacqueve, LM Saksida, TJ Bussey, BL Schneider, P Aebischer, R Melani, T Pizzorusso, JW Fawcett, MG Spillantini, Experimental Neurology 2015, 265, 48-58

Direct Observation of Propagating Gigahertz Coherent Guided Acoustic Phonons in Free Standing Single Copper Nanowires

We report on gigahertz acoustic phonon waveguiding in free-standing single copper nanowires studied by femtosecond transient reflectivity measurements. The results are discussed on the basis of the semianalytical resolution of the Pochhammer and Chree equation. The spreading of the generated Gaussian wave packet of two different modes is derived analytically and compared with the observed oscillations of the sample reflectivity. These experiments provide a unique way to independently obtain geometrical and material characterization. This direct observation of coherent guided acoustic phonons in a single nano-object is also the first step toward nanolateral size acoustic transducer and comprehensive studies of the thermal properties of nanowires