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Frontiers in Molecular Neuroscience 2021A typical neuron consists of a soma, a single axon with numerous nerve terminals, and multiple dendritic trunks with numerous branches. Each of the 100 billion neurons...
A typical neuron consists of a soma, a single axon with numerous nerve terminals, and multiple dendritic trunks with numerous branches. Each of the 100 billion neurons in the brain has on average 7,000 synaptic connections to other neurons. The neuronal endolysosomal compartments for the degradation of axonal and dendritic waste are located in the soma region. That means that all autophagosomal and endosomal cargos from 7,000 synaptic connections must be transported to the soma region for degradation. For that reason, neuronal endolysosomal degradation is an extraordinarily demanding and dynamic event, and thus is highly susceptible to many pathological conditions. Dysfunction in the endolysosomal trafficking pathways occurs in virtually all neurodegenerative diseases. Most lysosomal storage disorders (LSDs) with defects in the endolysosomal system preferentially affect the central nervous system (CNS). Recently, significant progress has been made in understanding the role that the endolysosomal trafficking pathways play after brain ischemia. Brain ischemia damages the membrane fusion machinery co-operated by N-ethylmaleimide sensitive factor (NSF), soluble NSF attachment protein (SNAP), and soluble NSF attachment protein receptors (SNAREs), thus interrupting the membrane-to-membrane fusion between the late endosome and terminal lysosome. This interruption obstructs all incoming traffic. Consequently, both the size and number of endolysosomal structures, autophagosomes, early endosomes, and intra-neuronal protein aggregates are increased extensively in post-ischemic neurons. This cascade of events eventually damages the endolysosomal structures to release hydrolases leading to ischemic brain injury. Gene knockout and selective inhibition of key endolysosomal cathepsins protects the brain from ischemic injury. This review aims to provide an update of the current knowledge, future research directions, and the clinical implications regarding the critical role of the neuronal endolysosomal trafficking pathways in ischemic brain injury.
PubMed: 34650402
DOI: 10.3389/fnmol.2021.719100 -
Frontiers in Medicine 2023Glioblastoma is the most common and malignant primary brain tumour with median survival of 14.6 months. Personalised medicine aims to improve survival by targeting...
INTRODUCTION
Glioblastoma is the most common and malignant primary brain tumour with median survival of 14.6 months. Personalised medicine aims to improve survival by targeting individualised patient characteristics. However, a major limitation has been application of targeted therapies in a non-personalised manner without biomarker enrichment. This has risked therapies being discounted without fair and rigorous evaluation. The objective was therefore to synthesise the current evidence on survival efficacy of personalised therapies in glioblastoma.
METHODS
Studies reporting a survival outcome in human adults with supratentorial glioblastoma were eligible. PRISMA guidelines were followed. MEDLINE, Embase, Scopus, Web of Science and the Cochrane Library were searched to 5th May 2022. Clinicaltrials.gov was searched to 25th May 2022. Reference lists were hand-searched. Duplicate title/abstract screening, data extraction and risk of bias assessments were conducted. A quantitative synthesis is presented.
RESULTS
A total of 102 trials were included: 16 were randomised and 41 studied newly diagnosed patients. Of 5,527 included patients, 59.4% were male and mean age was 53.7 years. More than 20 types of personalised therapy were included: targeted molecular therapies were the most studied (33.3%, 34/102), followed by autologous dendritic cell vaccines (32.4%, 33/102) and autologous tumour vaccines (10.8%, 11/102). There was no consistent evidence for survival efficacy of any personalised therapy.
CONCLUSION
Personalised glioblastoma therapies remain of unproven survival benefit. Evidence is inconsistent with high risk of bias. Nonetheless, encouraging results in some trials provide reason for optimism. Future focus should address target-enriched trials, combination therapies, longitudinal biomarker monitoring and standardised reporting.
PubMed: 37122327
DOI: 10.3389/fmed.2023.1166104 -
Frontiers in Immunology 2021Breast cancer (BC) prevention remains the ultimate cost-effective method to reduce the global burden of invasive breast cancer (IBC). To date, surgery and...
Breast cancer (BC) prevention remains the ultimate cost-effective method to reduce the global burden of invasive breast cancer (IBC). To date, surgery and chemoprevention remain the main risk-reducing modalities for those with hereditary cancer syndromes, as well as high-risk non-hereditary breast lesions such as ADH, ALH, or LCIS. Ductal carcinoma (DCIS) is a preinvasive malignant lesion of the breast that closely mirrors IBC and, if left untreated, develops into IBC in up to 50% of lesions. Certain high-risk patients with DCIS may have a 25% risk of developing recurrent DCIS or IBC, even after surgical resection. The development of breast cancer elicits a strong immune response, which brings to prominence the numerous advantages associated with immune-based cancer prevention over drug-based chemoprevention, supported by the success of dendritic cell vaccines targeting HER2-expressing BC. Vaccination against BC to prevent or interrupt the process of BC development remains elusive but is a viable option. Vaccination to intercept preinvasive or premalignant breast conditions may be possible by interrupting the expression pattern of various oncodrivers. Growth factors may also function as potential immune targets to prevent breast cancer progression. Furthermore, neoantigens also serve as effective targets for interception by virtue of strong immunogenicity. It is noteworthy that the immune response also needs to be strong enough to result in target lesion elimination to avoid immunoediting as it may occur in IBC arising from DCIS. Overall, if the issue of vaccine targets can be solved by interrupting premalignant lesions, there is a potential to prevent the development of IBC.
Topics: Animals; Antigens, Neoplasm; Breast Carcinoma In Situ; Breast Neoplasms; Cancer Vaccines; Carcinoma, Intraductal, Noninfiltrating; Disease Progression; Female; Humans; Neoplasm Invasiveness; Precancerous Conditions; Tumor Microenvironment; Vaccination
PubMed: 34899753
DOI: 10.3389/fimmu.2021.786286 -
Frontiers in Medicine 2021To conduct a systematic review and meta-analysis of the available research on evaluating changes in corneal dendritic cell density (CDCD) and the main subbasal nerve...
To conduct a systematic review and meta-analysis of the available research on evaluating changes in corneal dendritic cell density (CDCD) and the main subbasal nerve parameters (SNPs) on the ocular surface and assessing the diagnostic performance of confocal microscopy in patients with dry eye disease. A computerized systematic review of literature published in PUBMED, EMBASE, Web of Science, Scopus, and the Cochrane Central Register of Controlled Trials until May 8, 2020 was performed. All statistical analyses were conducted in software. The weighted mean differences (WMDs) and standardized mean differences (SMDs) with 95% confidence intervals (CI) between dry eye patients and healthy subjects were presented as results. A total of 11 studies with 755 participants were recruited, and 931 eyes were included in this meta-analysis. However, not all studies reported both CDCD and SNPs. CDCD in the central cornea was higher (WMD = 51.06, 95% CI = 39.42-62.71), while corneal nerve fiber density (CNFD) and corneal nerve fiber length (CNFL) were lower (WMD = -7.96, 95% CI = -12.12 to -3.81; SMD = -2.30, 95%CI = -3.26 to -1.35) in dry eye patients in comparison with the corresponding values in healthy controls (all < 0.00001). Taken together, while CNFD and CNFL were lower in dry eye patients, central CDCD showed a significant increase in these patients in comparison with the corresponding values in healthy controls.
PubMed: 33898473
DOI: 10.3389/fmed.2021.578233 -
Cytotherapy Oct 2019Although promising results have recently been reported using dendritic cells (DCs) and cytokine-induced killer cells (CIKs) to treat pancreatic cancer (PC), its clinical... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Although promising results have recently been reported using dendritic cells (DCs) and cytokine-induced killer cells (CIKs) to treat pancreatic cancer (PC), its clinical effect and safety are associated with some controversy, and lack sufficient evidence. Here, we conducted a meta-analysis of 21 clinical trials to better evaluate the efficacy of DC-CIK immunotherapy in clinical practice to treat PC.
METHODS
PubMed, Cochrane Library, China National Knowledge Infrastructure (CNKI) and Wanfang Data Knowledge Service Platform (WANFANG Data) were searched to identify clinical trials that used DC-CIK immunotherapy for PC. Meta-analysis was performed using RevMan 5.3 and Stata 12.0.
RESULTS
A total of 21 clinical trials involving 1549 patients were included. Compared with traditional treatment, DC-CIK immunotherapy improved and increased the clinical indices such as complete remission, partial remission, overall response rate, disease control rate, overall survival (0.5-y OS, 1-y OS, 1.5-y OS, 2-y OS and 3-y OS), interferon γ and CD3+, CD4+, CD4+/CD8+ and CD3+CD56+ lymphocyte. Additionally, DC-CIK immunotherapy reduced stable disease, progression disease, mortality, CD8+, CD4+CD25+CD127 low lymphocyte and interleukin-4. Furthermore, it showed a low incidence of adverse reactions (22%).
CONCLUSION
In contrast to traditional therapy, DC-CIK immunotherapy not only shows improved short-term effect, long-term effect and immunologic function, but also reduces mortality and negative immunoregulatory index, and shows mild adverse reactions. This is the first study to evaluate the clinical effect and safety of DC-CIK immunotherapy for PC, and it indicated that DC-CIK immunotherapy may be suitable for patients with advanced PC or intolerance to radiotherapy and chemotherapy.
Topics: Adult; Clinical Trials as Topic; Cytokine-Induced Killer Cells; Dendritic Cells; Humans; Immunotherapy, Adoptive; Pancreatic Neoplasms; Treatment Outcome
PubMed: 31462394
DOI: 10.1016/j.jcyt.2019.07.006 -
Current Molecular Medicine 2022Backgound and objective: Early chemoprevention in Oral Potentially Malignant Disorders (OPMDs) and Oral Cancer (OC) has been extensively researched in order to mitigate...
Backgound and objective: Early chemoprevention in Oral Potentially Malignant Disorders (OPMDs) and Oral Cancer (OC) has been extensively researched in order to mitigate the malignant transformation and progression of the lesion. Many agents have been attempted, but their cost inefficacy and inadequate outcomes posed a major hindrance in their successful adoption. Retinoid Based Therapy (RBT) though a cheap and effective treatment option, could not achieve much clinical usage because of variable responsiveness in clinical outcomes. Such clinical response variability may be attributed to the repression of retinoid receptors by Preferentially Expressed Antigen of Melanoma (PRAME) protein molecule. Therefore, in order to make RBT successful, targeting PRAME by various immunotherapies is an exciting area of research investigation. This review provides an insight into the various immunotherapeutic strategies targeting PRAME and their usefulness in retinoid-resistant OPMD and OC. Method of data collection: An exhaustive internet-based literature search following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines was carried out in PUBMED and Google SCHOLAR database using terms 'Anti-PRAME' OR 'PRAME Immunotherapy' OR 'PRAME Vaccines' AND 'Cancer' AND 'Retinoid resistance'. Only articles in the English language with at least 1 citation, published in a journal with impact factor ≥ 1, having relevance to the context and availability of full text were considered. Results: After an initial search, 342 articles were yielded on the basis of inclusion criteria and, by reading the abstract and availability of full text, a total of 124 articles were selected. Further reading the full texts and considering articles from the references of the selected articles, a total of 65 articles were finally included in the review. Conclusion: Our analysis of the literature suggests that PRAME screening in OC and OPMDs prior to RBT should be done. In PRAME positive cases, approaches like PRAME based immunotherapy in the form of Cancer vaccine therapy [Acellular PRAME vaccine, PRAME pulsed Dendritic Cells (DC)]; Adoptive T Cell therapy/T Cell Receptor-T Cell therapy, Antibody therapy/Chimeric Antigen Receptor-T Cell therapy along with Presented antigen modulation Therapies employing histone deacetylase inhibitors and demethylation agents seem plausible. In the future, a combination therapy employing either PRAME vaccines or antibodies or Adoptive T cell Therapy and ATRA could be used in retinoid resistant OC and OPMDs.
Topics: Antigens, Neoplasm; Humans; Immunotherapy; Mouth Neoplasms; Retinoids
PubMed: 34711164
DOI: 10.2174/1566524021666211027091719 -
Survey of Ophthalmology 2024Although there have been numerous innovations in the management of retinal detachment (RD) over the past decades, there is still limited understanding of the... (Review)
Review
Although there have been numerous innovations in the management of retinal detachment (RD) over the past decades, there is still limited understanding of the pathophysiological processes that take place before and after repair. Summarizing key concepts using animal studies may allow for a better assessment of common pre- and postoperative microstructural abnormalities in RD. We performed a systematic literature review on Ovid MEDLINE, EMBASE, and Cochrane Controlled Register of Trials from January 1968 to January 2022, searching animal or human studies reporting retinal histologic changes following primary or induced RD. Thirty-two studies were included. Main cellular events were summarized: photoceptor apoptosis occurs as early as 12 hours after RD and, although most cells survive, there is extensive remodeling. Outer segments progressively degenerate, while inner segments are reorganized. Rod and cone opsins are redistributed, and rod axons retract while cones undergo changes in shape. Second- and third-order neurons rearrange their dendritic processes, and Müller cells become hypertrophic, growing into the subretinal space. Finally, retinal pigment epithelium cells undergo a change in their morphology. Acknowledging critical morphologic changes following RD is crucial in understanding why anatomical and functional outcomes can vary. Insights from histological studies, together with high-resolution imaging, may be key in identifying novel biomarkers in RD.
Topics: Animals; Humans; Retinal Detachment; Retina; Retinal Cone Photoreceptor Cells; Retinal Degeneration
PubMed: 37652188
DOI: 10.1016/j.survophthal.2023.08.001 -
Frontiers in Molecular Neuroscience 2022Hyperpolarization-activated cyclic nucleotide-gated (HCN) current reduces dendritic summation, suppresses dendritic calcium spikes, and enables inhibitory GABA-mediated...
BACKGROUND
Hyperpolarization-activated cyclic nucleotide-gated (HCN) current reduces dendritic summation, suppresses dendritic calcium spikes, and enables inhibitory GABA-mediated postsynaptic potentials, thereby suppressing epilepsy. However, it is unclear whether increased HCN current can produce epilepsy. We hypothesized that gain-of-function (GOF) and loss-of-function (LOF) variants of HCN channel genes may cause epilepsy.
OBJECTIVES
This systematic review aims to summarize the role of HCN channelopathies in epilepsy, update genetic findings in patients, create genotype-phenotype correlations, and discuss animal models, GOF and LOF mechanisms, and potential treatment targets.
METHODS
The review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement, for all years until August 2021.
RESULTS
We identified pathogenic variants of ( = 24), ( = 8), ( = 2), and ( = 6) that were associated with epilepsy in 74 cases (43 , 20 , 2 , and 9 ). Epilepsy was associated with GOF and LOF variants, and the mechanisms were indeterminate. Less than half of the cases became seizure-free and some developed drug-resistant epilepsy. Of the 74 cases, 12 (16.2%) died, comprising ( = 4), ( = 2), ( = 2), and ( = 4). Of the deceased cases, 10 (83%) had a sudden unexpected death in epilepsy (SUDEP) and 2 (16.7%) due to cardiopulmonary failure. SUDEP affected more adults ( = 10) than children ( = 2). variants p.M234R, p.C329S, p.V414M, p.M153I, and p.M305L, as well as variants p.S632W and delPPP (p.719-721), were associated with different phenotypes. p.L157V and p.R550C were associated with genetic generalized epilepsy. There are several HCN animal models, pharmacological targets, and modulators, but precise drugs have not been developed. Currently, there are no HCN channel openers.
CONCLUSION
We recommend clinicians to include genes in epilepsy gene panels. Researchers should explore the possible underlying mechanisms for GOF and LOF variants by identifying the specific neuronal subtypes and neuroanatomical locations of each identified pathogenic variant. Researchers should identify specific HCN channel openers and blockers with high binding affinity. Such information will give clarity to the involvement of HCN channelopathies in epilepsy and provide the opportunity to develop targeted treatments.
PubMed: 35663267
DOI: 10.3389/fnmol.2022.807202 -
Expert Review of Vaccines Apr 2022Gliomas are major challenges of neuro-oncology due to high mortality. Clinical applications of dendritic cells (DCs) have yielded promising results in the clinical trial... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Gliomas are major challenges of neuro-oncology due to high mortality. Clinical applications of dendritic cells (DCs) have yielded promising results in the clinical trial pipelines over decades.
RESEARCH DESIGN
In this systematic review, we critically discuss the current status, future perspective, and challenges of DC therapy for gliomas . and summarize the study population, blinding, comparators, dosage, treatment regimens, efficacy, and safety issues of the clinical trials published on DC therapy for gliomas and also report the results of our meta-analysis on safety and immunological efficacy of DC therapy for gliomas.
RESULTS
The results of our meta-analysis indicated that the most frequent grade I/II adverse event (AE) reported in phase I or phase I/II trials was fatigue (∼16% and 24%). Moreover, in phase II trials, fatigue and cytopenia were the most common AEs (∼9% and 14%). Meanwhile, Grade III/IV AEs were rare . Moreover, our meta-analysis indicated ∼64% CD8+ T cells infiltration into tumor site after DC therapy and also ∼45% IFNγ increase.
CONCLUSIONS
DC therapy could serve as a potential immunotherapy for gliomas; however, limitations exist to draw certain conclusions due to diversity of the criteria applied to assess clinical response and limited data on patients' survival.
Topics: Brain Neoplasms; CD8-Positive T-Lymphocytes; Dendritic Cells; Glioma; Humans; Immunotherapy
PubMed: 35076331
DOI: 10.1080/14760584.2022.2027759 -
The Journal of Surgical Research Jun 2024Vascularized composite allotransplantation (VCA) is the transplantation of multiple tissue types as a solution for devastating injuries. Despite the highly encouraging... (Review)
Review
INTRODUCTION
Vascularized composite allotransplantation (VCA) is the transplantation of multiple tissue types as a solution for devastating injuries. Despite the highly encouraging functional outcomes of VCA, the consequences of long-term immunosuppression remain the main obstacle in its application. In this review, we provide researchers and surgeons with a summary of the latest advances in the field of cell-based therapies for VCA tolerance.
METHODS
Four electronic databases were searched: PubMed, Scopus, Cumulative Index to Nursing and Allied Health Literature , and Web of Science. We used the Preferred Reporting Items for Systematic Reviews and Meta-Analysis as the basis of our organization.
RESULTS
Hematopoietic stem cells prolonged VCA survival. A combination of immature dendritic cells and tacrolimus was superior to tacrolimus alone. T cell Ig domain and mucin domain modified mature dendritic cells increased VCA tolerance. Bone marrow-derived mesenchymal stem cells prolonged survival of VCAs. A combination of adipose-derived mesenchymal stem cells, cytotoxic T-lymphocyte antigen 4 immunoglobulin, and antilymphocyte serum significantly improved VCA tolerance. Ex-vivo allotransplant perfusion with recipient's bone marrow-derived mesenchymal stem cells increased VCA survival. Recipient's adipose-derived mesenchymal stem cells and systemic immunosuppression prolonged VCA survival more than any of those agents alone. Additionally, a combination of peripheral blood mononuclear cells shortly incubated in mitomycin and cyclosporine significantly improved VCA survival. Finally, a combination of donor recipient chimeric cells, anti-αβ-T cell receptor (TCR), and cyclosporine significantly prolonged VCA tolerance.
CONCLUSIONS
Evidence from animal studies shows that cell-based therapies can prolong survival of VCAs. However, there remain many obstacles for these therapies, and they require rigorous clinical research given the rarity of the subjects and the complexity of the therapies. The major limitations of cell-based therapies include the need for conditioning with immunosuppressive drugs and radiation, causing significant toxicity. Safety concerns also persist as most research is on animal models. While completely replacing traditional immunosuppression with cell-based methods is unlikely soon, these therapies could reduce the need for high doses of immunosuppressants and improve VCA tolerance.
PubMed: 38851085
DOI: 10.1016/j.jss.2024.04.079