Search

High-grade gliomas are a major health challenge with poor prognosis and high morbidity. Immune-checkpoint inhibitors (ICI) have emerged as promising therapeutic options for several malignancies yet show little efficacy against central nervous system (CNS) tumors. CD200 is a newly recognized immune checkpoint that modulates immune homeostasis. CD200 protein is expressed by a variety of cells, including immune cells and stromal cells, and is overexpressed by many tumors. The shedding of CD200 from tumor cells can create an immunosuppressive environment that dampens anti-tumor immunity by modulating cytolytic activity and cytokine expression both within and outside the tumor microenvironment (TME). While it is well-accepted that CD200 induces a pro-tumorigenic environment through its ability to suppress the immune response, we sought to determine the role of glioma-specific expression of CD200. We show that CD200 is expressed across glioma types, is shed from tumor cells, and increases over time in the serum of patients undergoing immunotherapy. Using CD200 knockout (KO) glioma models, we demonstrated that glioma cell-derived CD200 promotes tumor growth in vivo and in vitro. Notably, CD200 KO gliomas are spontaneously rejected by their host, a process that required a fully functional immune system, including NK and T-cells. Moreover, we report that glioma-derived or brain-injected soluble CD200 contributes to the suppression of antigen-specific CD8 T-cells in the draining lymph nodes (dLNs). Our work provides new mechanistic insights regarding CD200-mediated immunosuppression by gliomas., Statement of Significance: We demonstrate mechanisms of the druggable glioma-derived CD200 checkpoint on tumor growth and immune suppression.

Nanomedicine is a promising approach for tumor therapy but penetration is challenged by complex tumor microenvironments. The purpose of this study is to design nanoparticles and analyze their transport in two abnormal microenvironments through a 2-D simulation. Employing a Computational Fluid Dynamics (CFD) approach, tumor vascular-interstitial models were initially simulated, and the impact of nanoparticles on the velocity profile and pressure gradient within the tumor microenvironment was observed. Through meticulous mesh analysis, it was determined that optimal outcomes were achieved using a quadrilateral meshing method for pancreatic tumor and a quad/tri meshing method for hepatic tumor. Results showed an increase in vessel diameter correlated with elevated blood flow velocity, reaching a maximum of 1.40 × 10^-3 m/s with an expanding cell gap. The simulation results for pressure distribution show that as vessel diameter increases, the velocity of nanoparticles in blood increases and decreases the pressure of blood. Intriguingly, distinct fluid flow patterns in pancreatic and hepatic tumors, emphasize how microenvironmental differences, specifically cell pore size, profoundly impact therapeutic agent transport, with implications for drug delivery strategies in cancer therapy. These simulation-based insights enable researchers to anticipate nanofluid behavior in realistic settings. Future work, incorporating immune cells, will enhance the understanding of nanoparticle efficiency in cancer therapy., (© 2024. The Author(s).)

Pediatric high-grade gliomas (pHGGs) are the leading cause of cancer-related deaths in children in the USA. Sixteen percent of hemispheric pediatric and young adult HGGs encode Gly34Arg/Val substitutions in the histone H3.3 (H3.3-G34R/V). The mechanisms by which H3.3-G34R/V drive malignancy and therapeutic resistance in pHGGs remain unknown. Using a syngeneic, genetically engineered mouse model (GEMM) and human pHGG cells encoding H3.3-G34R, we demonstrate that this mutation led to the downregulation of DNA repair pathways. This resulted in enhanced susceptibility to DNA damage and inhibition of the DNA damage response (DDR). We demonstrate that genetic instability resulting from improper DNA repair in G34R-mutant pHGG led to the accumulation of extrachromosomal DNA, which activated the cyclic GMP-AMP synthase/stimulator of IFN genes (cGAS/STING) pathway, inducing the release of immune-stimulatory cytokines. We treated H3.3-G34R pHGG-bearing mice with a combination of radiotherapy (RT) and DNA damage response inhibitors (DDRi) (i.e., the blood-brain barrier-permeable PARP inhibitor pamiparib and the cell-cycle checkpoint CHK1/2 inhibitor AZD7762), and these combinations resulted in long-term survival for approximately 50% of the mice. Moreover, the addition of a STING agonist (diABZl) enhanced the therapeutic efficacy of these treatments. Long-term survivors developed immunological memory, preventing pHGG growth upon rechallenge. These results demonstrate that DDRi and STING agonists in combination with RT induced immune-mediated therapeutic efficacy in G34-mutant pHGG.

Glioblastoma (GBM) is an aggressive primary brain cancer, with a 5 year survival of ∼5%. Challenges that hamper GBM therapeutic efficacy include (i) tumor heterogeneity, (ii) treatment resistance, (iii) immunosuppressive tumor microenvironment (TME), and (iv) the blood-brain barrier (BBB). The C-X-C motif chemokine ligand-12/C-X-C motif chemokine receptor-4 (CXCL12/CXCR4) signaling pathway is activated in GBM and is associated with tumor progression. Although the CXCR4 antagonist (AMD3100) has been proposed as an attractive anti-GBM therapeutic target, it has poor pharmacokinetic properties, and unfavorable bioavailability has hampered its clinical implementation. Thus, we developed synthetic protein nanoparticles (SPNPs) coated with the transcytotic peptide iRGD (AMD3100-SPNPs) to target the CXCL2/CXCR4 pathway in GBM via systemic delivery. We showed that AMD3100-SPNPs block CXCL12/CXCR4 signaling in three mouse and human GBM cell cultures in vitro and in a GBM mouse model in vivo. This results in (i) inhibition of GBM proliferation, (ii) reduced infiltration of CXCR4 + monocytic myeloid-derived suppressor cells (M-MDSCs) into the TME, (iii) restoration of BBB integrity, and (iv) induction of immunogenic cell death (ICD), sensitizing the tumor to radiotherapy and leading to anti-GBM immunity. Additionally, we showed that combining AMD3100-SPNPs with radiation led to long-term survival, with ∼60% of GBM tumor-bearing mice remaining tumor free after rechallenging with a second GBM in the contralateral hemisphere. This was due to a sustained anti-GBM immunological memory response that prevented tumor recurrence without additional treatment. In view of the potent ICD induction and reprogrammed tumor microenvironment, this SPNP-mediated strategy has a significant clinical translation applicability.

COVID-19 vaccines have met varying levels of acceptance and hesitancy in different parts of the world, which has implications for eliminating the COVID-19 pandemic. The aim of this systematic review is to examine how and why the rates of COVID-19 vaccine acceptance and hesitancy differ across countries and continents. PubMed, Web of Science, IEEE Xplore and Science Direct were searched between 1 January 2020 and 31 July 2021 using keywords such as "COVID-19 vaccine acceptance". 81 peer-reviewed publications were found to be eligible for review. The analysis shows that there are global variations in vaccine acceptance among different populations. The vaccine-acceptance rates were the highest amongst adults in Ecuador (97%), Malaysia (94.3%) and Indonesia (93.3%) and the lowest amongst adults in Lebanon (21.0%). The general healthcare workers (HCWs) in China (86.20%) and nurses in Italy (91.50%) had the highest acceptance rates, whereas HCWs in the Democratic Republic of Congo had the lowest acceptance (27.70%). A nonparametric one-way ANOVA showed that the differences in vaccine-acceptance rates were statistically significant (H (49) = 75.302, p = 0.009*) between the analyzed countries. However, the reasons behind vaccine hesitancy and acceptance were similar across the board. Low vaccine acceptance was associated with low levels of education and awareness, and inefficient government efforts and initiatives. Furthermore, poor influenza-vaccination history, as well as conspiracy theories relating to infertility and misinformation about the COVID-19 vaccine on social media also resulted in vaccine hesitancy. Strategies to address these concerns may increase global COVID-19 vaccine acceptance and accelerate our efforts to eliminate this pandemic.

Gliomas are one of the most lethal types of cancers accounting for ∼80% of all central nervous system (CNS) primary malignancies. Among gliomas, glioblastomas (GBM) are the most aggressive, characterized by a median patient survival of fewer than 15  months. Recent molecular characterization studies uncovered the genetic signatures and methylation status of gliomas and correlate these with clinical prognosis. The most relevant molecular characteristics for the new glioma classification are IDH mutation, chromosome 1p/19q deletion, histone mutations, and other genetic parameters such as ATRX loss, TP53, and TERT mutations, as well as DNA methylation levels. Similar to other solid tumors, glioma progression is impacted by the complex interactions between the tumor cells and immune cells within the tumor microenvironment. The immune system's response to cancer can impact the glioma's survival, proliferation, and invasiveness. Salient characteristics of gliomas include enhanced vascularization, stimulation of a hypoxic tumor microenvironment, increased oxidative stress, and an immune suppressive milieu. These processes promote the neuro-inflammatory tumor microenvironment which can lead to the loss of blood-brain barrier (BBB) integrity. The consequences of a compromised BBB are deleteriously exposing the brain to potentially harmful concentrations of substances from the peripheral circulation, adversely affecting neuronal signaling, and abnormal immune cell infiltration; all of which can lead to disruption of brain homeostasis. In this review, we first describe the unique features of inflammation in CNS tumors. We then discuss the mechanisms of tumor-initiating neuro-inflammatory microenvironment and its impact on tumor invasion and progression. Finally, we also discuss potential pharmacological interventions that can be used to target neuro-inflammation in gliomas., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Alghamri, McClellan, Hartlage, Haase, Faisal, Thalla, Dabaja, Banerjee, Carney, Mujeeb, Olin, Moon, Schwendeman, Lowenstein and Castro.)

Visceral leishmaniasis (VL)-related mortality and morbidity imposes a great deal of health concern across the globe. The existing anti-leishmanial drug regimen generally fails to eliminate newly emerging resistant isolates of this dreadful parasite. In such circumstances, the development of a prophylactic strategy to impart protection against the disease is likely to take center stage. In order to develop a promising prophylactic vaccine, it is desirable to identify an adequately potential vaccine candidate. In silico analysis of Leishmania tubulin folding cofactor D protein predicted its potential to activate both B- and T-cell repertoires. Furthermore, the ELISA employing anti-peptide 27 (a segment of tubulin folding cofactor D) antibody revealed its proficiency in VL diagnosis and treatment monitoring. The peptide 27 and its cocktail with another Leishmania peptide (peptide 23 ) prompted the up-regulation of pro-inflammatory cytokines, such as IFN-γ, TNF-α, IL-2, IL-17, etc ., and the down-regulation of immune-regulatory cytokines, such as IL-10, in the immunized BALB/c mice. Coherent to the consequence of peptide-specific humoral immune response, peptide cocktail-based immunization ensued in the predominant amplification of pathogen-specific IgG2a over the IgG1 isotype, up-regulated proliferation of T lymphocytes, and enhanced production of nitric oxide, reactive oxygen species, etc . We also established that the peptide cocktail modulated host MAPK signaling to favor the amplification of Th 1 -dominated immune response in the host. The peptide cocktail mediated the activation of the host immune armory, which was eventually translated into a significant decline in parasitic load in the visceral organs of experimental animals challenged with Leishmania donovani ., (Copyright © 2020 Jamal, Singh, Hansa, Pushpanjali, Ahmad, Dikhit, Umar, Bimal, Das, Mujeeb, Singh, Zubair and Owais.)

In the present study, we have synthesized silver-copper nanocomposites (Ag-Cu NCs) using an Olax scandens leaf extract (green synthesis method) and evaluated their antimicrobial potential against less susceptible pathogens. The kinetics of Ag-Cu NCs synthesis was followed by UV-VIS and fluorescence spectroscopy. The physicochemical characterization of as-synthesized Ag-Cu NCs was executed using electron microscopy, Energy Dispersive X-Ray, Fourier Transform Infrared Spectroscopy, and a Differential Light Scattering method. As-synthesized Ag-Cu NCs induced the formation of Reactive Oxygen Species (ROS), thereby causing alteration and decrementation of cellular proteins, DNA, lipids, etc., and eventually leading to cell death, as determined by a Live/Dead assay. Next, we assessed the anti-biofilm potential of as-synthesized Ag-Cu NCs against biofilm forming bacteria. The as-synthesized Ag-Cu NCs, when compared to monometallic silver nanoparticles, exhibited significantly higher anti-microbial activity against both sensitive as well as drug resistant microbial isolates., (Copyright © 2020 Mujeeb, Khan, Jamal, Badre Alam, Saeed, Kazmi, Alshameri, Kashif, Ghazi and Owais.)

In general, neurodegenerative disorders have a great deal of correlation with the misfolded as well as aggregated forms of protein-based macromolecules. Among various species formed during the aggregation process, protein oligomers have been classified as most toxic entities against several types of living cells. A series of chemicals have been developed to inhibit protein aggregation as a measure to regulate neurodegenerative diseases. Recently, various classes of nanoparticles have also been reported to inhibit protein aggregation. In the present study, we synthesized fluorescent gold nanoparticles (B-AuNPs) employing Olax scandens leaf extract. Next, an in vitro study was performed to assess the effect of as-synthesized B-AuNPs on the aggregation behavior of the ovalbumin (OVA) and other related model proteins. We performed an extensive study to elucidate anti-amyloidogenic properties of nano-sized entities and established that small-sized B-AuNPs manifest chaperone potential against protein aggregation. Further, we exploited as-synthesized B-AuNPs as a mean to prevent protein aggregation mediated toxicity in neuroblastoma cells., (Copyright © 2019 Mujeeb, Alam, Alshameri, Jamal, Farheen, Kashif, Ahmed, Ghazi and Owais.)

Nano-sized drug delivery systems (NDDS) have been widely exploited to achieve targeted delivery of pharmaco-materials. Traditional pharmaceutical approaches, implied in the synthesis of nano-formulations, are obscure owing to the incompatible physico-chemical properties of the core drug as well as some other factors crucial in development of NDDS. Infact, most of the existing methods used in development of NDDS rely on usage of additives or excipients, a special class of chemicals. Barring few exceptions, the usage of synthetic excipients ought to be curtailed because of several associated undesirable features. Such issues necessitate strategies that lead to development of the synthetic excipient free drug delivery system. Plant based extracts have great potential to induce synthesis of nano-sized particles. Considering this fact, here we propose a prototype employing orange fruit juice (OJ) to facilitate bio-mediated synthesis of nano-sized supra-molecular assemblies of 5-fluorouracil (5-FU), a potent anticancer drug. The as-synthesized 5-FU Nanoparticles (NPs) retained the anti-neoplastic efficacy of the parent compound and induced apoptosis in cancer cells. The novel 5-FU NPs formulation demonstrated enhanced efficacy against DMBA induced experimental fibrosarcoma in the mouse model when compared to the micro-sized crystals of parent 5-FU drug.

A previously healthy 6-year-old boy was referred to us by his primary provider, with a history of sudden onset behavioural abnormalities including irritability, sleep disturbance and anxiety. Physical examination revealed no significant findings; further analyses were not suggestive of meningitis, encephalitis, metabolic abnormalities, toxicity or any other obvious cause. On rechecking the patient's history, an episode of throat pain 1 week prior to the symptom onset was noted. Therefore, the possibility of paediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) was considered. The antistreptolysin O titre was high (1078 IU/mL), and it increased to 1194 IU/mL 4 weeks later, leading to a diagnosis of PANDAS. He was started on ampicillin and administered one dose of intravenous immunoglobulin. His abnormal behaviours subsided and he returned to a normal state within 48 hours of treatment. This report aims to provide insights into the symptomology and diagnosis of PANDAS in children., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Amyloids are highly organized fibril aggregates arise from inappropriately folded form of the protein or polypeptide precursors under both physiological as well as simulated ambience. Amyloid synthesis is a multistep process that involves formation of several metastable intermediates. Among various intermediate species, the as-formed soluble oligomers are extremely toxic to the neuronal cells. In the present study, we evaluated cyclosporine A (CsA), an undecapeptide, for its potential to prevent aggregation of model protein ovalbumin (OVA). In an attempt to elucidate involved operative mechanism, the preliminary studies delineate that CsA affects both primary nucleation as well as other secondary pathways involved in OVA fibrillation process. By its specific interaction with amyloid intermediates, the cyclic peptide CsA seems to regulate the lag phase of the fibrillation process in concentration dependent manner. The present study further suggests that exposure to CsA during lag phase ensues in reversal of OVA fibrillation process. On the contrary, mature OVA fibril remained impervious to the CsA treatment. The cyclic undecapeptide CsA was also found to successfully alleviate amyloid induced toxicity in neuroblastoma cells.