In-vivo Exposure Research Articles

Intensive Cognitive-Behavioral Therapy for Anxiety Disorders in Adolescents: A Case Study

Anxiety disorders are one of the most common psychiatric conditions in youth and can contribute to impairment in social, academic, and family functioning. Cognitive-behavioral therapy (CBT) has been shown to be efficacious in treating youth anxiety disorders; however, for a multitude of reasons, fewer than 20% of adolescents with anxiety disorders receive services for anxiety-related problems. Intensive treatments, which rely on the same traditional components of CBT but are delivered over a shorter period of time or in a fewer number of sessions, may be particularly helpful for anxiety disorders and can offer a number of advantages over standard CBT. Despite emerging evidence supporting the advantages of the intensive approach, there are few established intensive treatment programs for youth with anxiety disorders. Further, no treatment to date has comprehensively targeted the entire spectrum of comorbid adolescent anxiety disorders in a combined intensive and transdiagnostic format, even though non-intensive (i.e., weekly delivered) CBT has been tested using a transdiagnostic approach. We developed an intensive, six-session intervention based on Angelosante and colleagues’ 2009 The Adolescent Panic Control Treatment with In-Vivo Exposures (Angelosante et al., 2009) and other empirically-supported treatments for youth to target all anxiety disorders in adolescents. We present a case study on an adolescent with multiple comorbid anxiety and related disorders who received intensive CBT treatment as a way to illustrate the clinical benefit and utility of an intensive, transdiagnostic approach. Findings support the acceptability and feasibility of transdiagnostic treatment of youth anxiety.

An anti-CTLA-4 heavy chain–only antibody with enhanced Treg depletion shows excellent preclinical efficacy and safety profile

The value of anti-CTLA-4 antibodies in cancer therapy is well established. However, the broad application of currently available anti-CTLA-4 therapeutic antibodies is hampered by their narrow therapeutic index. It is therefore challenging and attractive to develop the next generation of anti-CTLA-4 therapeutics with improved safety and efficacy. To this end, we generated fully human heavy chain-only antibodies (HCAbs) against CTLA-4. The hIgG1 Fc domain of the top candidate, HCAb 4003-1, was further engineered to enhance its regulatory T (Treg) cell depletion effect and to decrease its half-life, resulting in HCAb 4003-2. We tested these HCAbs in invitro and invivo experiments in comparison with ipilimumab and other anti-CTLA4 antibodies. The results show that human HCAb 4003-2 binds human CTLA-4 with high affinity and potently blocks the binding of B7-1 (CD80) and B7-2 (CD86) to CTLA-4. The results also show efficient tumor penetration. HCAb 4003-2 exhibits enhanced antibody-dependent cellular cytotoxicity function, lower serum exposure, and more potent anti-tumor activity than ipilimumab in murine tumor models, which is partly driven by a substantial depletion of intratumoral Tregs. Importantly, the enhanced efficacy combined with the shorter serum half-life and less systemic drug exposure invivo potentially provides an improved therapeutic window in cynomolgus monkeys and preliminary clinical applications. With its augmented efficacy via Treg depletion and improved safety profile, HCAb 4003-2 is a promising candidate for the development of next generation anti-CTLA-4 therapy.

Effectiveness of Technology-Based Interventions for Scrupulous Obsessions and Compulsions: A Case Report

Introduction: Cognitive-behavioral therapy (CBT) is one of the most important well-known treatments for obsessive-compulsive disorder (OCD), including the scrupulosity type. Technology-based interventions can increase the effects of CBT by different methods. The aim of this study was to examine the effectiveness of online cognitive therapy in a Muslim patient with scrupulosity employing in-vivo exposure, with the therapist virtually present and using a treatment application. Case Presentation: The patient was a 37-year-old female diagnosed with scrupulosity in OCD by a psychiatrist. The patient’s symptoms were measured at baseline for 6 weeks then underwent 12 sessions of CBT with the therapist present via video call. All the exposure sessions were conducted in real situations triggering thoughts and compulsions. The therapy application was also used between sessions as an assistive treatment tool. Conclusions: The results of this treatment model showed a decrease in obsessive symptoms and beliefs and anxiety and depression symptoms at the end of treatment and after a 3-month follow-up. Moreover, the quality of life was improved in the patient.

Abstract 419: The development of BRPF1 degraders as a potential treatment for acute myeloid leukemia

Abstract Acetylation of histones and additional nuclear proteins is a key mechanism in the regulation of gene expression. Aberrant acetylation has been linked to a wide range of diseases including cancer, inflammation, and neurodevelopmental disorders. Histone acetylation is introduced by histone acetyltransferases complexes (HATs), where substrate specificity is dramatically enhanced by scaffolding proteins that activate and target them to specific chromatin sites. A protein of interest with both epigenetic acetyl reader and scaffolding function is the protein Bromodomain and PHD finger-containing protein 1 (BRPF1). The Protein contains domains of two plant homeodomain (PHD) fingers separated by a zinc knuckle (PZP domain), a bromodomain, and a proline-tryptophan-tryptophan-proline (PWWP) Tudor domain. Native BRPF1 complexes can contain either MOZ/MORF or HBO1 as the catalytic MYST-family acetyltransferase subunit and the stable complex with Moz-Tif2 is known to lead to the development of human acute myeloid leukemia (AML). Given this, we chose to pursue the development of BRPF1 degraders to probe cancer disease biology especially in AML, where new therapies are required to overcome several unmet needs such as less-toxic treatments and relapsed/refractory disease paradigms. Here we present the design and synthesis of a range of BRPF1 degraders in highly desirable physicochemical space utilizing in-silico modeling. The prepared degraders which utilize multiple E3 ligases were then screened against cell lines harboring Mixed-lineage leukemia (MLL) translocations specifically the THP-1 cell line. In addition to this, we investigated the ability of the compounds to effectively degrade the target and suitability of our degraders for potential in-vivo exposure through a panel of routine ADMET assays. Citation Format: Daniel Joseph Glynn, Rosie Crampton, Thomas Pesnot, Andrew Scott, Anne-Chloe Nassoy, Ralph Kirk, Daniele Narducci, Gary Nelson, Lynette Ongiri, Habiba Begum, Vincent Rao, Matilda Bingham, Rhoanne McPherson, Darryl Turner. The development of BRPF1 degraders as a potential treatment for acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 419.

Biomarker Responses, Gene Expression Alterations, and Histological Changes in Zebrafish (Danio rerio) After In Vivo Exposure to Polychlorinated Diphenyl Ethers.

Polychlorinated diphenyl ethers (PCDEs) have been detected in various aquatic matrices, which pose potential threats to aquatic ecosystem security. In this work, both micro and macro analysis methods were used to assess the toxicity of PCDEs to zebrafish. Results indicated that after in vivo PCDE exposure, the oxidative stress and related gene of Danio rerio were significantly changed. The higher concentration or longer exposure time could cause more severe oxidative stress in zebrafish tissues. Compared with among the five tested compounds, more obvious changes in the level of oxidative biomarkers of lower chlorinated PCDEs’ (4-mono-CDE and 4,4′-di-CDE) exposure groups were observed. The integrated biomarker response analysis and gene expression results also indicate a similar trend. Histopathological observation suggested that 4,4′-di-CDE could render liver nuclei enlargement and necrosis, hepatocyte vacuolation, and the development inhibition of ovarian cells. Transmission electron microscope photos showed that 4,4′-di-CDE caused organelle damage in the liver and ovary, including the rupture of the endoplasmic reticulum, swelling of mitochondria, and condensation of chromatin in the liver and mitochondria disappeared significantly in the ovary. The degree of damage is enhanced with the increasing exposure doses. In addition, PCDEs also significantly altered vitellogenin content and related gene (vtg1) expression, suggesting that PCDEs may be estrogen endocrine disruptors. Overall, these results provided some valuable toxicological data of PCDEs on aquatic species.

A Case Report of Home-Based Cognitive-Behavioural Treatment for Late-Onset Post-Traumatic Stress Disorder, Triggered by Mask-Wearing in the Context of the COVID-19 Pandemic.

A small but clinically significant number of people experience delayed-onset Post-traumatic stress disorder (PTSD); symptoms of trauma years after the events which are now being re-experienced. The following case report describes the use of the cognitive-behavioural treatment for PTSD with a woman experiencing flashbacks to domestic abuse endured more than 20 years ago. Mask-wearing mandated as a result of the COVID-19 pandemic triggered non-contextualised memories of life-threatening physical violence by an abuser who covered his face. She had been managing her flashbacks and intrusive thoughts with both behavioural and experiential forms of avoidance. An 18-session intervention was provided in her own home due to physical health difficulties. Treatment focused on managing hyper-arousal, reducing thought suppression, in-vivo exposure, stimulus-discrimination and re-contextualising traumatic memories. Regular outcome measurements were kept and results are presented as a single-case experimental design in ‘AB’ format (i.e. baseline period pre intervention). Symptoms of trauma fell to levels non-indicative of PTSD and speak to the evidence base for this modality, even when applied to delayed-onset difficulties in a non-traditional therapy setting. This conclusion is lent extra credence by an experimental design with good internal validity.

Changes in the Number of Mesenchymal Stem Cells in Bone Marrow at Different Periods after In Vivo Exposure of the Bone Marrow to Local Infrared Laser Radiation.

We determined optimal parameters of bone marrow (BM) irradiation in vivo for rapid increase in the number of mesenchymal stem cells (MSC) at the initial stages of the culturing without changing the karyotype, polyploidy, which are observed at higher passages. Such an increase is necessary to achieve the required number of cells at the initial passages for subsequent transplantation into the body. It was shown that after irradiation with λ=0.97 μm, the maximum and similar increase in the content of BM MSC in comparison with the control (by 2.4 times) was observed on day 2 in the irradiated and contralateral tibia. An insignificant difference in the number of BM MSC for the irradiated and contralateral tibia remained at all terms after irradiation, with a general decrease in the number of BM MSC up to 21 days. After laser irradiation with λ=1.56 μm, the maximum number of BM MSC was also observed on day 2. In this case, the concentration of these cells in the irradiated and contralateral limbs exceeded the control by 3.1 and 1.7 times, respectively. With increasing the time after exposure, the number of BM MSC in both limbs showed the same tendency to a decrease as after irradiation at λ=0.97 μm.

Development and Evaluation of Nanoparticles-in-Film Technology to Achieve Extended In Vivo Exposure of MK-2048 for HIV Prevention.

MK-2048 is a second-generation integrase inhibitor active against HIV, which has been applied vaginally using ring formulations. In this work, a nanoparticle-in-film technology was developed as a discrete pre-exposure prophylactic product option against HIV for an extended duration of use. A film platform loaded with poly (lactic-co-glycolic acid) nanoparticles (PNP) encapsulating MK-2048 was engineered. MK-2048 PNPs were loaded into films that were manufactured via the solvent casting method. Physicochemical and mechanical properties, in vitro efficacy, Lactobacillus compatibility, in vitro and ex vivo permeability, and in vivo pharmacokinetics in macaques were evaluated. PNPs with a mean diameter of 382.2 nm and −15.2 mV zeta potential were obtained with 95.2% drug encapsulation efficiency. PNP films showed comparable in vitro efficacy to free MK-2048 (IC50 0.46 vs. 0.54 nM) and were found to have no impact on Lactobacillus. MK-2048 encapsulated in PNPs showed an increase in permeability (>4-fold) compared to the free MK-2048 in MDCKII cell lines. Furthermore, PNPs had higher ectocervical tissue permeability (1.7-fold) compared to free MK-2048. PNP films showed sustained drug levels for at least 3 weeks in the macaque vaginal fluid. This work demonstrates the synergy of integrating nanomedicine and polymeric film technology to achieve sustained vaginal drug delivery.

High Doses of Pesticides Induce mtDNA Damage in Intact Mitochondria of Potato In Vitro and Do Not Impact on mtDNA Integrity of Mitochondria of Shoots and Tubers under In Vivo Exposure.

It is well known that pesticides are toxic for mitochondria of animals. The effect of pesticides on plant mitochondria has not been widely studied. The goal of this research is to study the impact of metribuzin and imidacloprid on the amount of damage in the mtDNA of potato (Solanum tuberosum L.) in various conditions. We developed a set of primers to estimate mtDNA damage for the fragments in three chromosomes of potato mitogenome. We showed that both metribuzin and imidacloprid considerably damage mtDNA in vitro. Imidacloprid reduces the rate of seed germination, but does not impact the rate of the growth and number of mtDNA damage in the potato shoots. Field experiments show that pesticide exposure does not induce change in aconitate hydratase activity, and can cause a decrease in the rate of H2O2 production. We can assume that the mechanism of pesticide-induced mtDNA damage in vitro is not associated with H2O2 production, and pesticides as electrophilic substances directly interact with mtDNA. The effect of pesticides on the integrity of mtDNA in green parts of plants and in crop tubers is insignificant. In general, plant mtDNA is resistant to pesticide exposure in vivo, probably due to the presence of non-coupled respiratory systems in plant mitochondria.

Individual Patterns and Temporal Trajectories of Changes in Fear and Pain during Exposure In Vivo: A Multiple Single-Case Experimental Design in Patients with Chronic Pain.

Exposure in vivo (EXP) is an effective treatment to reduce pain-related fear and disability in chronic pain populations. Yet, it remains unclear how reductions in fear and pain relate to each other. This single-case experimental design study attempted to identify patterns in the individual responses to EXP and to unravel temporal trajectories of fear and pain. Daily diaries were completed before, during and after EXP. Multilevel modelling analyses were performed to evaluate the overall effect. Temporal effects were scrutinized by individual regression analyses and determination of the time to reach a minimal clinically important difference. Furthermore, individual graphs were visually inspected for potential patterns. Twenty patients with chronic low back pain and complex regional pain syndrome type I were included. On a group level, both fear and pain were reduced following EXP. Individually, fear was significantly reduced in 65% of the patients, while pain in only 20%. A decrease in fear was seen mostly in the first weeks, while pain levels reduced later or remained unchanged. Daily measurements provided rich data on temporal trajectories of reductions in fear and pain. Overall, reductions in fear preceded pain relief and seemed to be essential to achieve pain reductions.

Effects of body ownership illusion during exposure to disgusting stimuli

BackgroundThe Rubber Hand Illusion (RHI) refers to the feeling of ownership of a rubber hand by synchronously stroking the rubber hand and the own hand of a person. Previous research has shown that RHI can be used to simulate skin contact with a disgust-eliciting stimulus. We used a primary disgust elicitor (a living maggot) to replicate this finding and to gather data on disgust habituation during RHI, and effects on in-vivo exposure. MethodsA total of 82 healthy participants (25 males, 57 females) were randomly assigned to one of two conditions; synchronous stroking or asynchronous stroking (control condition) of the rubber/own hand. Subsequently, a maggot was placed on the rubber hand for five minutes. Participants rated experienced disgust at the beginning and end of the exposure. They were also asked if the maggot could be placed on their own hand. ResultsSynchronous stroking successfully elicited RHI, which was associated with higher disgust ratings for the maggot at the beginning of exposure compared to asynchronous stroking. The two conditions did not differ in disgust habituation and the willingness to expose the own hand to the maggot. ConclusionRHI successfully simulated skin contact with a disgust stimulus. Future studies should apply longer exposure intervals and test individuals with higher disgust propensity to detect possible RHI effects on disgust habituation.

Tribocorrosion Susceptibility and Mechanical Characteristics of As-Received and Long-Term In-Vivo Aged Nickel-Titanium and Stainless-Steel Archwires.

To evaluate the effect of long-term in-vivo aging on orthodontic archwires, we aimed to assess the triboelectrochemical and mechanical characteristics of as-received and in-vivo aged nickel-titanium (NiTi) and stainless-steel (SS) orthodontic archwires. Four consecutive tribocorrosion cycles on six NiTi and six SS archwires, as-received and in-vivo aged, were performed on a reciprocal tribometer. Electrochemical noise and friction coefficient measurements, three-dimensional surface profiling, and hardness measurements were performed. Repassivation times of as-received archwires were longer than of the in-vivo aged; however, were shorter for NiTi. Friction coefficients were higher for NiTi than for SS archwires. Sudden major current drops concomitant with inverse potential shifts and friction coefficients’ fluctuations, were seen for as-received (last cycle) and in-vivo aged (last three cycles) NiTi archwires. More pronounced tribocorrosion damage was observed on in-vivo aged NiTi than on other archwires. Hardness was generally higher inside the wear track of archwires. Long-term in-vivo exposure decreases the corrosion susceptibility of archwires, more evidently for the NiTi ones. Sudden major fluctuations in electrochemical current, potential, and friction coefficient detected for NiTi archwires, might be related to localized residual parts of the oxide layer persisting due to increased surface roughness or to phase transformations of the alloy’s crystal structure.

Exposure in Vivo as a Treatment Approach to Target Pain-Related Fear: Theory and New Insights From Research and Clinical Practice

For patients with chronic pain who have elevated pain-related fear (PRF), exposure is the treatment of choice. This Perspective highlights the inhibitory learning approach, summarizes mechanistic work from experimental psychology and neuroimaging regarding PRF in chronic pain, and describes possible clinical applications of EXP in chronic secondary pain as well as in primary care.

Comparison of the effect of in vitro and in vivo exposure on cadaveric anxiety among first year medical and nursing students

BACKGROUND:Human anatomy instruction is mostly focused on cadaver dissection and prosected specimen examination. Exposure to cadaver dissection can be a stressful experience that may cause a wide variety of symptoms among students of health sciences. To compare and evaluate the effect of in-vitro and in-vivo exposure on cadaveric anxiety, disgust propensity and sensitivity, and attitude toward death and dying among 1st-year medical and nursing students.MATERIALS AND METHODS:An open-label randomized trial (matched-control experimental design) was conducted among 127 1st-year Medical and Nursing students from a selected Institute of National Importance, Bhopal, India during 2015. The participants were divided into an experimental and control group based on matched trait anxiety scores using the Trait Anxiety Inventory. Followed by preassessment, video demonstration with cadaver dissection (in vitro exposure) was then administered to the experimental group, while the control group had direct exposure to cadaver dissection (in vivo exposure).RESULTS:The study showed that there was a statistically significant difference in state anxiety related to cadaver dissection in the experimental group (P = 0.01). However, video-demonstration of cadaver dissection did not have any effect on disgust propensity and sensitivity and attitude toward death and dying.CONCLUSION:The findings provided evidence that video-demonstration of cadaver dissection reduced anxiety, although it did not have any effect on disgust and attitudes of death. The dissection hall experience may evoke feelings of anxiety and disgust that need to be addressed through advanced preparedness and coping strategies, especially among medical and nursing students.

The First Steps in Facing Your Fears the Acceptability of Virtual Reality and in Vivo Exposure Treatment for Specific Fears

The First Steps in Facing Your Fears the Acceptability of Virtual Reality and in Vivo Exposure Treatment for Specific Fears

Provider experiences of virtual reality in clinical treatment.

BackgroundVirtual reality (VR) has proven effective in the treatment of specific phobias and trauma particularly when in-vivo exposure therapy might be costly (e.g. fear of flying, combat scenes). Similarly, VR has been associated with improvement of chronic pain and of acute pain during medical procedures. Despite its effectiveness as a healthcare tool, VR technology is not well-integrated into common practice. This qualitative study aims to explore the provider perception of the value of VR and identify barriers to VR implementation among healthcare providers.MethodsA 66-item self-report survey was created to examine application of VR to clinical practice, perceived value of this treatment, ease of learning the technology, billing considerations, and other obstacles. 128 providers (MDs and PhDs) who were located in the United States and had used VR as a therapeutic tool in the past year were identified through research papers, as well as user lists and news articles from VR application websites. Of the 128 providers contacted, 17% (22) completed our online self-report measure. Of these, 13% of respondents (N = 17) completed greater than 75% of the questionnaire and were considered completers. Provider responses were collected over a one-month period and qualitatively analyzed.ResultsThe majority of providers were from an academic institution (n = 12, 70.6%), and all providers practiced in the outpatient setting. Providers most commonly reported using VR for the treatment of acute pain and/or anxiety related to medical procedures (n = 11, 64.7%), followed by specific phobia (n = 6, 35.3%) and social phobia (n = 6, 35.3%). All providers agreed VR is a valuable tool they would recommend to colleagues. The majority (n = 15, 93.8%) believed VR helped their patients progress in treatment, compared with other methods. Providers cited the ability to individualize treatment (n = 14, 87.5%) and increase patient engagement (n = 15, 93.8%) as main benefits of VR. A minority reported negative feedback from patients about content (n = 4, 25%) or about the technology in general (n = 6, 37.5%), whereas all reported some form of positive feedback. The slight majority (n = 10, 58.8%) of providers did not find transitioning to VR difficult. Of those who did, cost was the most commonly cited barrier (n = 6). Regarding reimbursement, only 17.6% (n = 3) of providers reported the ability to bill for VR sessions. Most providers (n = 15, 88.2%) received training on their VR platform which they found beneficial. Comparing the trained and untrained groups found no significant difference in VR comfort level (p = 0.5058), the value of VR in practice (p = 0.551) or whether providers would recommend VR to others (p = 0.551), though sample sizes were small.ConclusionsIn corroboration with previous research, this study demonstrates that VR is well-received by patients and providers, allowing increased patient engagement and treatment individualization. However, associated costs, including an inability to bill for this service, can present a barrier to further implementation. These findings will guide further development of virtual reality as a standardized tool in psychiatry and pain management.

Stable Epigenetic Programming of Effector and Central Memory CD4 T Cells Occurs Within 7 Days of Antigen Exposure In Vivo.

T cell immunological memory is established within days of an infection, but little is known about the in vivo changes in gene regulatory networks accounting for their ability to respond more efficiently to secondary infections. To decipher the timing and nature of immunological memory we performed genome-wide analyses of epigenetic and transcriptional changes in a mouse model generating antigen-specific T cells. Epigenetic reprogramming for Th differentiation and memory T cell formation was already established by the peak of the T cell response after 7 days. The Th memory T cell program was associated with a gain of open chromatin regions, enriched for RUNX, ETS and T-bet motifs, which remained stable for 56 days. The epigenetic programs for both effector memory, associated with T-bet, and central memory, associated with TCF-1, were established in parallel. Memory T cell-specific regulatory elements were associated with greatly enhanced inducible Th1-biased responses during secondary exposures to antigen. Furthermore, memory T cells responded in vivo to re-exposure to antigen by rapidly reprograming the entire ETS factor gene regulatory network, by suppressing Ets1 and activating Etv6 expression. These data show that gene regulatory networks are epigenetically reprogrammed towards memory during infection, and undergo substantial changes upon re-stimulation.

Is Continued Improvement After Automated Virtual Reality Exposure Therapy for Spider Phobia Explained by Subsequent in-vivo Exposure? A First Test of the Lowered Threshold Hypothesis.

Consumer Virtual Reality (VR) technology offers a powerful, immersive medium for scalable dissemination of mental health interventions. Decades of research has shown VR exposure therapy to be efficacious in the treatment of anxiety disorders and that the fear reduction generalizes to real-world stimuli. Many studies also report continued improvement over time, after discontinuing VR use. The lowered threshold hypothesis states that this continued improvement is moderated by lowering the threshold to conduct subsequent in-vivo exposure. The current study is the first to formally test this hypothesis, using data from a recent trial on automated VR exposure therapy for spider phobia, in which participants (n = 49) were followed for 1 year, completing assessments 1 week, 3 and 12 months post-treatment. The assessment included validated self-report of phobia symptoms, a standardized behavioral approach test featuring a real spider, and a questionnaire for self-reporting frequency of in-vivo exposures since last assessment. Number of in-vivo exposures was found to be independently associated with greater symptom decrease in longitudinal outcome models. In sequential structural equation models, immediate post-treatment symptom reduction was associated with subsequent in-vivo exposures, which in turn was associated with continued symptom reduction. However, this applied only to self-reported phobia symptoms (not behavioral avoidance) and no associations were found past 3 months. Our findings offer preliminary, partial support for the lowered threshold hypothesis, suggesting that VR exposure interventions may benefit from including explicit in-virtuo to in-vivo transitioning components.

A Meta-Analysis of the Efficacy of Virtual Reality and In Vivo Exposure Therapy as Psychological Interventions for Public Speaking Anxiety.

Public speaking anxiety (PSA) is a prevalent condition with disabling occupational, educational, and social consequences. Exposure therapy is a commonly utilized approach for treating PSA. Traditionally, this intervention has been delivered as in vivo exposure therapy (IVET). Limitations inherent to in vivo as a mode of delivery have been identified and studies have increasingly explored the use of Virtual Reality Exposure Therapy (VRET) as an alternative. Understanding the efficacy of both VRET and IVET as psychological interventions for PSA is important. A systematic search identified 11 studies with 508 participants. Meta-analysis yielded a large significant effect wherein VRET resulted in significant reductions in PSA versus control of −1.39 (Z = 3.96, p < .001) and a similar large significant effect wherein IVET resulted in significant reductions in PSA versus control of −1.41 (Z = 7.51, p < .001). Although IVET was marginally superior to VRET, both interventions proved efficacious. Given the advantages of utilizing VRET over IVET future research and clinical practice could explore VRET as a treatment option for PSA.

Toll-Like Receptor Expression of Mesenchymal Stem Cells Derived from Granulocyte Colony-Stimulating Factor Treated Bone Marrow Donors

Objective: The present study was planned to examine the expression of Toll-like receptors on human marrow-derived mesenchymal stem cells as a result of in-vivo exposure to granulocyte colony-stimulating factor with or without exposure of the cells to Toll-like receptors agonists.&#x0D; Materials and Methods: Toll-like receptor 2, 3, and 4 expressions of mesenchymal stem cells obtained from healthy human bone marrow donors exposed to in-vivo granulocyte colony-stimulating factor were analyzed, and granulocyte colony-stimulating factor untreated donors served as controls. Also, mesenchymal stem cells were stimulated in-vitro by Toll-like receptor agonists to observe the changes in the expression of the Toll-like receptors.&#x0D; Results: Mesenchymal stem cells obtained from both granulocyte colony-stimulating factor exposed or unexposed donors showed a low level of Toll-like receptor 2, 4 expressions by flow cytometry, whereas Toll-like receptor 3 expression was higher. Lipopolysaccharide was used as an agonist, but no significant difference was observed in the Toll-like receptor 2, 4 expressions, both in the granulocyte colony-stimulating factor exposed and unexposed groups. Stimulation of cells with Toll-like receptor 3 ligand was associated with a statistically significant decrease in Toll-like receptor 3 expressions, which was more profound in granulocyte colony-stimulating factor unexposed cells.&#x0D; Conclusion: We have shown that human bone marrow-derived culture-expanded mesenchymal stem cells express Toll-like receptor 3, whether in-vivo granulocyte colony-stimulating factor treated or untreated. Besides, the Toll-like receptor 3 agonist’s effect in lowering the expression levels was more significant in cells that were not exposed to granulocyte colony-stimulating factor. Additionally, detection of low expression of the pro-inflammatory Toll-like receptor 4 versus higher levels of Toll-like receptor 3 supports literature regarding the immunosuppressive characteristics of marrow-derived mesenchymal stem cells. Modulation of the expression of the Toll-like receptor of mesenchymal stem cells with granulocyte colony-stimulating factor or agonists may have implications in allogeneic mesenchymal stem cell therapies.