Distinct Regulation of Th17 and Th1 Cell Differentiation by Glutaminase-Dependent Metabolism.

Activated T cells differentiate into functional subsets with distinct metabolic programs. Glutaminase (GLS) converts glutamine to glutamate to support the tricarboxylic acid cycle and redox and epigenetic reactions. Here, we identify a key role for GLS in T cell activation and specification. Though GLS deficiency diminished initial T cell activation and proliferation and impaired differentiation of Th17 cells, loss of GLS also increased Tbet to promote differentiation and effector function of CD4 Th1 and CD8 CTL cells. This was associated with altered chromatin accessibility and gene expression, including decreased PIK3IP1 in Th1 cells that sensitized to IL-2-mediated mTORC1 signaling. In vivo, GLS null T cells failed to drive Th17-inflammatory diseases, and Th1 cells had initially elevated function but exhausted over time. Transient GLS inhibition, however, led to increased Th1 and CTL T cell numbers. Glutamine metabolism thus has distinct roles to promote Th17 but constrain Th1 and CTL effector cell differentiation.

Activation of T cell checkpoint pathways during ß-cell antigen presentation by engineered dendritic cells promotes protection from type 1 diabetes.

Defective immune regulation has been recognized in type 1 diabetes (T1D). Immune regulatory T cell check-point receptors, which are generally upregulated on activated T cells, have been the molecules of attention as therapeutic targets for enhancing immune response in tumour therapy. Here, we show that pancreatic ß-cell antigen (BcAg) presentation by engineered tolerogenic dendritic cells (tDCs) that express CTLA4 selective ligand (B7.1wa) or a combination of CTLA4, PD1 and BTLA selective ligands (B7.1wa, PD-L1 and HVEM-CRD1 respectively; multiligand-DCs) causes an increase in regulatory cytokine and T cell (Treg) responses and suppression of the effector T cell function as compared with engineered control-DCs. Non-obese diabetic mice treated with BcAg-pulsed CTLA4-ligand-DCs and multiligand-DCs at pre-diabetic and early-hyperglycaemic stages showed significantly lower degree of insulitis, higher frequencies of insulin-positive islets, profound delay in and reversal of hyperglycaemia for a significant duration. Immune cells from the tDC-treated mice not only produced lower amounts of IFNγ and higher amounts of IL10 and TGFß1 upon BcAg challenge, but also failed to induce hyperglycaemia upon adoptive transfer. While both CTLA4-ligand-DCs and multiligand-DCs were effective in inducing tolerance, multiligand-DC treatment produced an overall higher suppressive effect on effector T cell function and disease outcome. These studies show that enhanced engagement of T cell checkpoint receptors during BcAg presentation can modulate T cell function and suppress autoimmunity and progression of the disease in T1D.

Decreased expression of protein O-linked mannose ß-1,2-N-acetylglucosaminyltransferase 1 contributes to Alzheimer's disease-like pathologies.

Alzheimer's disease (AD) is pathologically characterized by senile plaques and neurofibrillary tangles composed of ß-amyloid peptide (Aß) and tau hyperphosphorylation, respectively. Mannosylation, a particular type of posttranslational modification, may be involved in the pathogenesis of AD. However, its underlying mechanism remains unclear. Protein O-linked mannose ß-1,2-N-acetylglucosaminyltransferase 1 (POMGnT1) catalyzes the formation of the N-acetylglucosamine ß-1,2-Man linkage of O-mannosylglycan, which can increase the protein posttranslational mannosylation level. The defective POMGnT1 gene leads to the hypomannosylation of proteins, which may cause cognitive decline in aged people. This study aimed to investigate whether POMGnT1 participated in the pathogenesis of AD and explore its underlying role using AD mouse and cell models. In this study, the expression of POMGnT1 was measured in AD models [ß-amyloid precursor protein (APP)/presenilin-1 (PS1) transgenic mice, an AD mouse model; N2a cells stably transfected with Swedish mutant APP (N2a/APP), an AD cell model]. The results revealed that the expression of POMGnT1 decreased in AD mouse and cell models. In addition, POMGnT1-overexpressing N2a/APP cells were built by retroviral transfection. POMGnT1 overexpression may lower Aß levels by reducing APP production and downregulating ß- and γ-secretase activities. It also promoted clearance of Aß by upregulating insulin-degrading enzymes and ameliorated tau hyperphosphorylation. Hence, it was concluded that POMGnT1 was involved in the pathogenic process of AD. The decreased expression of POMGnT1 contributes to AD-like pathologies.NEW & NOTEWORTHY This study explored the role of mannosylation in the pathogenesis of AD through a mannosyltransferase-POMGnT1. Results demonstrated that target gene overexpression could ameliorate pathologies of Aß and tau hyperphosphorylation. This study is the first to examine the relationship between mannosylation and AD.

Clinical effect of successful reperfusion in patients presenting with NIHSS < 6 and large vessel occlusion.

PURPOSE: The purpose of this study was to evaluate the impact of reperfusion in patients with large vessel occlusion (LVO) of the anterior circulation and National Institutes of Health Stroke Scale (NIHSS)< 6. METHODS: It was a retrospective cohort study. The reperfusion grade was determined using the modified thrombolysis in cerebral infarction (TICI) score. The modified Rankin Score (mRS) ≤1 were defined as excellent and (mRS) ≤2 as favorable outcome at 3-month. Meanwhile, the all-cause mortality, intracerebral hemorrhage, and complications were recorded. Multivariate logistic regression analyses were performed to evaluate outcomes. RESULTS: Seventy-six patients (86.4%) achieved reperfusion (TICI2B/3). Excellent outcome was achieved in 62 (70.5%) and favorable outcome in 69 (78.4%). All-cause death occurred in 2 (2.3%). The rate of excellent outcome in patients with TICI0,1,2A was 41.7%, with TICI2B 69.2%, and with TICI3 78.0% (p < 0.05). In a multivariate logistic regression analysis related to excellent outcome, the OR(95% CI) was 5.68(1.35,23.95) for TICI3; the test for linear trend by entering categorical variables as continuous variables in the adjusted model (p for trend=0.02<0.05), defining TICI0,1,2A as reference. Subgroup analyses showed without intravenous thrombolysis (IVT) (OR, 14.29; 95% CI, 1.76-116.37) and with middle cerebral artery (MCA) occlusion (OR, 7.97; 95% CI,1.26-50.32), the excellent outcome further improved with TICI3. Findings were similar in favorable outcome. CONCLUSIONS: Our results indicated that successful reperfusion was intensely connected with better functional outcomes for patients with LVO presenting with NIHSS<6 in the anterior circulation, especially MCA occlusion and pretreatment without IVT.

Carnosic acid promotes degradation of the androgen receptor and is regulated by the unfolded protein response pathway in vitro and in vivo.

Androgen deprivation therapy in prostate cancer is extremely effective; however, due to the continuous expression and/or mutagenesis of androgen receptor (AR), the resistance to antihormonal therapy is a natural progression. Consequently, targeting the AR for degradation offers an alternate approach to overcome this resistance in prostate cancer. In this study, we demonstrate that carnosic acid, a benzenediol diterpene, binds the ligand-binding domain of the AR and degrades the AR via endoplasmic reticulum (ER) stress-mediated proteasomal degradative pathway. In vitro, carnosic acid treatment induced degradation of AR and decreased expression of prostate-specific antigen in human prostate cancer cell lines LNCaP and 22Rv1. Carnosic acid also promoted the expression of ER proteins including BiP and CHOP in a dose-dependent manner. Downregulation of CHOP by small interfering RNA somewhat restored expression of AR suggesting that AR degradation is dependent on ER stress pathway. Future studies will need to evaluate other aspects of the unfolded protein response pathway to characterize the regulation of AR degradation. Furthermore, cotreating cells individually with carnosic acid and proteasome inhibitor (MG-132) and carnosic acid and an ER stress modulator (salubrinal) restored protein levels of AR, suggesting that AR degradation is mediated by ER stress-dependent proteasomal degradation pathway. Degradation of AR and induction of CHOP protein were also evident in vivo along with a 53% reduction in growth of xenograft prostate cancer tumors. In addition, carnosic acid-induced ER stress in prostate cancer cells but not in normal prostate epithelial cells procured from patient biopsies. In conclusion, these data suggest that molecules such as carnosic acid could be further evaluated and optimized as a potential therapeutic alternative to target AR in prostate cancer.

Inhibition of CHOP accentuates the apoptotic effect of α-mangostin from the mangosteen fruit (Garcinia mangostana) in 22Rv1 prostate cancer cells.

The mangosteen (Garcinia mangostana) fruit has been a popular food in Southeast Asia for centuries and is increasing in popularity in Western countries. We identified α-Mangostin as a primary phytochemical modulating ER stress proteins in prostate cancer cells and propose that α-Mangostin is responsible for exerting a biological effect in prostate cancer cells. Two human prostate cancer cell lines, 22Rv1 and LNCaP, and prostate epithelial cells procured from two patients undergoing radical prostatectomy were treated with α-Mangostin and evaluated by RT-PCR, Western blot, fluorescent microscopy and siRNA transfection to evaluate ER stress. Next, we evaluated α-Mangostin for microsomal stability, pharmacokinetic parameters, and anti-cancer activity in nude mice. α-Mangostin significantly upregulated ER stress markers in prostate cancer cells. Interestingly, α-Mangostin did not promote ER stress in prostate epithelial cells (PrECs) from prostate cancer patients. CHOP knockdown enhanced α-Mangostin-induced apoptosis in prostate cancer cells. α-Mangostin significantly suppressed tumor growth in a xenograft tumor model without obvious toxicity. Our study suggests that α-Mangostin is not the only active constituent from the mangosteen fruit requiring further work to understand the complex chemical composition of the mangosteen.

Systemic lupus erythematosus and epilepsy: A Mendelian randomization study.

OBJECTIVE: Numerous observational studies have found a relationship between systemic lupus erythematosus (SLE) and epilepsy; however, their causal relationship remains unclear. This study aimed to investigate the causal role of SLE in epilepsy or any of its subtypes using a two-sample Mendelian randomization (MR) analysis. METHODS: Single nucleotide polymorphisms (SNPs) linked to SLE were utilized as instrumental variables in MR analysis to assess their causal impact on epilepsy. The primary MR findings were derived using the inverse variance weighted (IVW) method, which was further supported by the weighted median and MR-Egger regression techniques. Additionally, sensitivity analyses, including Cochran's Q test and pleiotropy tests, were conducted to evaluate the influence of these SNPs on epilepsy, particularly looking for signs of horizontal pleiotropy and heterogeneity. RESULTS: We selected 43 SNPs that reached genome-wide significance from genome-wide association studies (GWASs) on SLE to serve as instrumental variables in this study. The IVW method showed no evidence to support a causal association between SLE and epilepsy (all epilepsy: odds ratio (OR) = 1.006, 95% confidence interval (CI) = 0.994-1.018; focal epilepsy: OR = 1.006, 95% CI = 0.994-1.019; generalized epilepsy: OR = 1.015, 95% CI = 0.996-1.035). Other MR complementary methods revealed consistent results. Furthermore, there was no evidence indicating heterogeneity or horizontal pleiotropy. SIGNIFICANCE: The findings of MR analysis did not support a genetically predicted causal relationship between SLE and epilepsy, but emphasized the need for further research on shared pathophysiological mechanisms, particularly the role of immune system abnormalities and potential influences such as chronic inflammation and therapeutic interventions. PLAIN LANGUAGE SUMMARY: The etiology of epilepsy is complex and diverse, including immune factors. Through a Mendelian randomization analysis, we did not find evidence of a genetic causal relationship between systemic lupus erythematosus and epilepsy. However, this does not invalidate epidemiological evidence, and further exploration is needed to investigate factors influencing the relationship between the two.

Sex and race differences in the association of albumin with cognitive function in older adults.

BACKGROUND: With the increasing aging population, dementia has become a significant socioeconomic burden. However, the effects of albumin on delayed recall (DR) impairment remain unclear, and there are limited reports on sex and race differences in this relationship. This study aimed to investigate the association between albumin levels and DR impairment in older adults. METHODS: A total of 1507 normal cognitive function and 553 DR impairment from the National Health and Nutrition Examination Survey (NHANES) 2011-2014 were included in this cross-sectional analysis. Participants aged 60 years and above were assessed using the Consortium to Establish a Registry for Alzheimer's Disease DR (CERAD-DR) test to evaluate cognitive function. Participants were categorized into DR impairment and normal cognitive function groups according to their CERAD-DR scores. Logistic regression analyses, generalized additive models, and fitted smoothing curves were utilized for data analysis. RESULTS: After adjusting for potential confounders, a negative association was found between albumin levels and cognitive function (odds ratio [OR] = 0.60, 95% confidence interval [CI] 0.41-0.87). Subgroup analysis stratified by sex, race/ethnicity, and age revealed that the negative association remained significant in men (OR = 0.53, 95%CI 032-0.87), Blacks (OR = 0.35, 95%CI 0.17-0.74), and the age group of 60-70 years (OR = 0.48, 95%CI 0.28-0.81). However, no significant association was observed in women (OR = 0.72, 95%CI 0.41-1.28), whites (OR = 0.58, 95%CI 0.31-1.07), or Mexican Americans (OR = 1.11, 95%CI 0.35-3.46), as well as the age group of 71-80 years (OR = 0.62, 95%CI 0.37-1.03). CONCLUSIONS: Our study suggests that elevated albumin levels are associated with a decreased incidence of cognitive function impairment, particularly in older men and Blacks. This finding indicates that maintaining high levels of albumin may be beneficial for cognitive function in older adults.

The association between HDL-C and stroke in the middle-aged and elderly: A cross-sectional study.

BACKGROUND: Previous epidemiological studies have indicated that high-density lipoprotein cholesterol (HDL-C) is inversely associated with the risk of cardiovascular disease. However, this issue has aroused controversy in recent years. Besides, the relationship between HDL-C and the risk of total stroke in sex and race is less clear. Thus, we aimed to examine the association between different ranges of HDL-C and the risk of total stroke in adults over 40 years old. METHODS: This cross-sectional study was conducted on a sample of 8643 participants (4222 men and 4421 women) aged ≥40 years old from the National Health and Nutrition Examination Survey 2007-2016. HDL-C was an independent variable and stroke was a dependent variable in this study, with the other variables as potential effect modifiers. To examine the associations between them, we used multivariate logistical regression models and smooth curve fittings, as well as subgroup analyses. RESULTS: HDL-C was inversely associated with stroke when HDL-C was less than 1.55 mmol/L (odds ratio [OR] = 0.36, 95% confidence interval [CI] :0.21-0.62, p < .05). However, above 1.55 mmol/L, the incidence of stroke was not significant (OR = 1.29, 95% CI: 0.79-2.09, p>.05). Stratified by race/ethnicity and sex, the subgroup analyses demonstrated that HDL-C was inversely associated with stroke in men and Whites, but no significant differences among women, Mexicans, blacks, and other races. CONCLUSION: We found a nonlinear relationship between HDL-C and total stroke. Our study reveals a range of inverse associations between HDL-C and stroke (HDL-C<1.55 mmol/L), especially among men and Whites. This finding suggested that maintaining an appropriate HDL-C range may be beneficial in reducing the incidence of stroke.

Underwater Undulating Propulsion Biomimetic Robots: A Review.

The traditional propeller-based propulsion of underwater robots is inefficient and poorly adapted to practice. By contrast, underwater biomimetic robots show better stability and maneuverability in harsh marine environments. This is particularly true of undulating propulsion biomimetic robots. This paper classifies the existing underwater biomimetic robots and outlines their main contributions to the field. The propulsion mechanisms of underwater biomimetic undulating robots are summarized based on theoretical, numerical and experimental studies. Future perspectives on underwater biomimetic undulating robots are also presented, filling the gaps in the existing literature.

Chaihu-Longgu-Muli decoction improves sleep disorders by restoring orexin-A function in CKD mice.

Introduction: Chaihu-Longgu-Muli decoction (CLMD) is a well-used ancient formula originally recorded in the "Treatise on Febrile Diseases" written by the founding theorist of Traditional Chinese Medicine, Doctor Zhang Zhongjing. While it has been used extensively as a therapeutic treatment for neuropsychiatric disorders, such as insomnia, anxiety and dementia, its mechanisms remain unclear. Methods: In order to analyze the therapeutic mechanism of CLMD in chronic renal failure and insomnia, An adenine diet-induced chronic kidney disease (CKD) model was established in mice, Furthermore, we analyzed the impact of CLMD on sleep behavior and cognitive function in CKD mice, as well as the production of insomnia related regulatory proteins and inflammatory factors. Results: CLMD significantly improved circadian rhythm and sleep disturbance in CKD mice. The insomnia related regulatory proteins, Orexin, Orexin R1, and Orexin R2 in the hypothalamus of CKD mice decreased significantly, while Orexin and its receptors increased remarkably after CLMD intervention. Following administration of CLMD, reduced neuron loss and improved learning as well as memory ability were observed in CKD mice. And CLMD intervention effectively improved the chronic inflflammatory state of CKD mice. Discussion: Our results showed that CLMD could improve sleep and cognitive levels in CKD mice. The mechanism may be related to the up-regulation of Orexin-A and increased phosphorylation level of CaMKK2/AMPK, which further inhibits NF-κB downstream signaling pathways, thereby improving the disordered inflammatory state in the central and peripheral system. However, More research is required to confirm the clinical significance of the study.

Large Scale Ex Vivo Expansion of γδ T cells Using Artificial Antigen-presenting Cells.

Higher γδ T cell counts in patients with malignancies are associated with better survival. However, γδ T cells are rare in the blood and functionally impaired in patients with malignancies. Promising results are reported on the treatment of various malignancies with in vivo expansion of autologous γδ T cells using zoledronic acid (zol) and interleukin-2 (IL-2). Here we demonstrated that zol and IL-2, in combination with a novel genetically engineered K-562 CD3scFv/CD137L/CD28scFv/IL15RA quadruplet artificial antigen-presenting cell (aAPC), efficiently expand allogeneic donor-derived γδ T cells using a Good Manufacturing Practice (GMP) compliant protocol sufficient to achieve cell doses for future clinical use. We achieved a 633-fold expansion of γδ T cells after day 10 of coculture with aAPC, which exhibited central (47%) and effector (43%) memory phenotypes. In addition, >90% of the expanded γδ T cells expressed NKG2D, although they have low cell surface expression of PD1 and LAG3 inhibitory checkpoint receptors. In vitro real-time cytotoxicity analysis showed that expanded γδ T cells were effective in killing target cells. Our results demonstrate that large-scale ex vivo expansion of donor-derived γδ T cells in a GMP-like setting can be achieved with the use of quadruplet aAPC and zol/IL-2 for clinical application.

Upregulation of ski in fibroblast is implicated in the peroxisome proliferator--activated receptor δ-mediated wound healing.

BACKGROUND/AIM: Both peroxisome proliferator-activated receptor (PPAR) δ and Ski are investigate the interaction of PPARδ and Ski and this interaction-associated effect in wound healing. METHODS: Effect of PPARδ activation on Ski expression was detected in rat skin fibroblasts by real-time PCR and western blot. Luciferase assay, electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) assay were performed to identify the binding site of PPARδ in the promoter region of rat Ski gene. And the functional activity of PPARδ regulation to Ski was detected in fibroblast proliferation and rat skin wound healing model. RESULTS: PPARδ agonist GW501516 upregulated Ski expression in a dose-dependent manner. Direct repeat-1 (DR1) response element locating at -865∼-853 in Ski promoter region was identified to mediate PPARδ binding to Ski and associated induction of Ski. Furthermore, PPARδ upregulated Ski to promote fibroblasts proliferation and rat skin wound repair, which could be largely blocked by pre-treated with Ski RNA interference. CONCLUSION: This study demonstrates that Ski is a novel target gene for PPARδ and upregulation of Ski to promote fibroblast proliferation is implicated in the PPARδ-mediated wound healing.

Gastrin producing syngeneic mesenchymal stem cells protect non-obese diabetic mice from type 1 diabetes.

Progressive destruction of pancreatic islet ß-cells by immune cells is a primary feature of type 1 diabetes (T1D) and therapies that can restore the functional ß-cell mass are needed to alleviate disease progression. Here, we report the use of mesenchymal stromal/stem cells (MSCs) for the production and delivery of Gastrin, a peptide hormone that is produced by intestinal cells and foetal islets and can increase ß-Cell mass, to promote protection from T1D. A single injection of syngeneic MSCs that were engineered to express Gastrin (Gastrin-MSCs) caused a significant delay in hyperglycaemia in non-obese diabetic (NOD) mice compared to engineered control-MSCs. Similar treatment of early-hyperglycaemic mice caused the restoration of euglycemia for a considerable duration, and these therapeutic effects were associated with the protection of, and/or higher frequencies of, insulin-producing islets and less severe insulitis. While the overall immune cell phenotype was not affected profoundly upon treatment using Gastrin-MSCs or upon in vitro culture, pancreatic lymph node cells from Gastrin-MSC treated mice, upon ex vivo challenge with self-antigen, showed a Th2 and Th17 bias, and diminished the diabetogenic property in NOD-Rag1 deficient mice suggesting a disease protective immune modulation under Gastrin-MSC treatment associated protection from hyperglycaemia. Overall, this study shows the potential of production and delivery of Gastrin in vivo, by MSCs, in protecting insulin-producing ß-cells and ameliorating the disease progression in T1D.

In-situ growing of metal-organic frameworks on iron mesh as a recyclable remediation material for removing hexavalent chromium from groundwater.

The recovery and reuse of adsorbents is crucial for the effectiveness and sustainability of mitigation methods for groundwater pollution. Considering the difficulty in recovering powder materials and the low mechanical strength of membrane materials, we developed a sheet material with good recyclability and certain mechanical strength. In this study, an in situ synthesized MIL-100(Fe) film sample was produced by hydrothermal reaction using a commercially available iron mesh as the substrate. The MIL-100(Fe) samples were characterized by SEM, XRD, XPS, and FT-IR. The experiments showed that the material presented excellent removal ability toward Cr(VI) and good recovery performance. In the fourth cycle test, the Cr(VI) removal rate reached more than 95%. The material characterization and adsorption kinetics indicated that the removal mechanism was oxidation-reduction reaction and electrostatic adsorption. The removal experiments at different pH values and with different co-existing ions demonstrated that the material can maintain good removal capacity at pH values between 2 and 8, and common ions in groundwater can promote the removal of Cr(VI) under neutral conditions. The recycling test demonstrated that the sample can be reused. After the sample was recovered and calcined in an inert environment, a network sample containing zero-valent iron was obtained, and it removed Cr(VI) from water at a low pH in 20 min. This study provides a new alternative for the practical removal of Cr(VI) from groundwater.

CD3 engagement as a new strategy for allogeneic "off-the-shelf" T cell therapy.

Allogeneic "off-the-shelf" (OTS) chimeric antigen receptor T cells (CAR-T cells) hold promise for more accessible CAR-T therapy. Here, we report a novel and simple way to make allogeneic OTS T cells targeting cancer. By engineering T cells with a bispecific T cell engager (BiTE), both TCRαß and CD3ε expression on the T cell surface are dramatically reduced. BiTE-engineered T (BiTE-T) cells show reduced reaction to TCR stimulation in vitro and have low risk of graft-versus-host disease (GvHD) in vivo. BiTE-T cells down-regulated CD3ε/TCRαß on bystander T cells by releasing BiTEs. BiTE-T cells produce much fewer cytokines and are comparable to CAR-T cells on anti-cancer efficacy in xenograft mouse models with pre-existing HLA-mismatched T cells. Co-expressing co-stimulatory factors or T cell-promoting cytokines enhanced BiTE-T cells. Our study suggests CD3ε engagement could be a new strategy for allogeneic T cell therapy worthy of further evaluation.

Emerging CAR T Cell Strategies for the Treatment of AML.

Engineered T cells expressing chimeric antigen receptors (CARs) on their cell surface can redirect antigen specificity. This ability makes CARs one of the most promising cancer therapeutic agents. CAR-T cells for treating patients with B cell hematological malignancies have shown impressive results. Clinical manifestation has yielded several trials, so far five CAR-T cell therapies have received US Food and Drug Administration (FDA) approval. However, emerging clinical data and recent findings have identified some immune-related toxicities due to CAR-T cell therapy. Given the outcome and utilization of the same proof of concept, further investigation in other hematological malignancies, such as leukemias, is warranted. This review discusses the previous findings from the pre-clinical and human experience with CAR-T cell therapy. Additionally, we describe recent developments of novel targets for adoptive immunotherapy. Here we present some of the early findings from the pre-clinical studies of CAR-T cell modification through advances in genetic engineering, gene editing, cellular programming, and formats of synthetic biology, along with the ongoing efforts to restore the function of exhausted CAR-T cells through epigenetic remodeling. We aim to shed light on the new targets focusing on acute myeloid leukemia (AML).

A Window of Opportunity to Overcome Therapeutic Failure in Neuro-Oncology.

Glioblastoma is the most common primary malignant brain neoplasm and it remains one of the most difficult-to-treat human cancers despite decades of discovery and translational and clinical research. Many advances have been made in our understanding of the genetics and epigenetics of gliomas in general; yet, there remains an urgent need to develop novel agents that will improve the survival of patients with this deadly disease. What sets glioblastoma apart from all other cancers is that it develops and spreads within an organ that renders tumor cells inaccessible to most systemically administered agents because of the presence of the blood-brain barrier. Inadequate drug penetration into the central nervous system is often cited as the most common cause of trial failure in neuro-oncology, and even so-called brain-penetrant therapeutics may not reach biologically relevant concentrations in tumor cells. Evaluation of the pharmacokinetics and pharmacodynamics of a novel therapy is a cornerstone of drug development, but few trials for glioma therapeutics have incorporated these basic elements in an organ-specific manner. Window-of-opportunity clinical trial designs can provide early insight into the biological plausibility of a novel therapeutic strategy in the clinical setting. A variety of window-of-opportunity trial designs, which take into account the limited access to treated tissue and the challenges with obtaining pretreatment control tissues, have been used for the initial development of traditional and targeted small-molecule drugs and biologic therapies, including immunotherapies and oncolytic viral therapies. Early-stage development of glioma therapeutics should include a window-of-opportunity component whenever feasible.

Myeloid Cell Classification and Therapeutic Opportunities Within the Glioblastoma Tumor Microenvironment in the Single Cell-Omics Era.

The glioma tumor microenvironment (TME) is complex and heterogeneous, and multiple emerging and current technologies are being utilized for an improved comprehension and understanding of these tumors. Single cell analysis techniques such as single cell genomic and transcriptomic sequencing analysis are on the rise and play an important role in elucidating the glioma TME. These large datasets will prove useful for patient tumor characterization, including immune configuration that will ultimately influence therapeutic choices and especially immune therapies. In this review we discuss the advantages and drawbacks of these techniques while debating their role in the domain of glioma-infiltrating myeloid cells characterization and function.

[PPARγ up-regulates TGFß/smad signal pathway repressor c-Ski].

TGFß/smad pathway is recognized as an important signal pathway to promote the pathogenesis of atherosclerosis (AS). Peroxisome proliferator-activated receptor γ (PPARγ) activation is considered to be important in modulating AS. Herein, we investigated the regulation of PPARγ on c-Ski, the repressor of TGFß/smad pathway, in rat AS model and cultured vascular smooth muscle cells (VSMCs). c-Ski mRNA and protein expression were detected by real-time PCR and Western blot, respectively, in vivo and in vitro with treatment of PPARγ agonist rosiglitazone and antagonist GW9662. The proliferation and collagen secretion of VSMCs after c-Ski transfection were investigated. The underlying mechanism was further investigated by online program NUBIScan and luciferase reporter gene analysis. Results showed that both mRNA and protein expressions of c-Ski in the AS lesions was down-regulated in vivo, while in cultured VSMCs, c-Ski transfection significantly suppressed the proliferation and collagen secretion of rat VSMCs. Rosiglitazone significantly up-regulated mRNA and protein levels of c-Ski in VSMCs, which could be blocked by GW9662. Online NUBIScan analysis suggested possible PPARγ binding sites in the promoter region of c-Ski. In addition, luciferase activity of c-Ski reporter gene was also increased obviously in the presence of rosiglitazone. These results indicate that c-Ski is one of the newly found target genes of PPARγ and thus involved in the anti-AS effect of PPARγ.