Tumor-associated macrophages affect the treatment of lung cancer.

As one of the most common malignant tumors in the world, lung cancer has limited benefits for patients despite its diverse treatment methods due to factors such as personalized medicine targeting histological type, immune checkpoint expression, and driver gene mutations. The high mortality rate of lung cancer is partly due to the immune-suppressive which limits the effectiveness of anti-cancer drugs and induces tumor cell resistance. The currently widely recognized TAM phenotypes include the anti-tumor M1 and pro-tumor M2 phenotypes. M2 macrophages promote the formation of an immune-suppressive microenvironment and hinder immune cell infiltration, thereby inhibiting activation of the anti-tumor immune system and aiding tumor cells in resisting treatment. Analyzing the relationship between different treatment methods and macrophages in the TME can help us better understand the impact of TAMs on lung cancer and confirm the feasibility of targeted TAM therapy. Targeting TAMs to reduce the M2/M1 ratio and reverse the immune-suppressive microenvironment can improve the clinical efficacy of conventional treatment methods and potentially open up more efficient combination treatment strategies, maximizing the benefit for lung cancer patients.

Feasibility and safety of EGFR-TKI neoadjuvant therapy for EGFR-mutated NSCLC: A meta-analysis.

BACKGROUND: The role of neoadjuvant epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) targeted therapy for EGFR-mutated non-small cell lung cancer (NSCLC) is unclear. Previous studies have shown that EGFR-TKIs have excellent anti-tumor activity. However, almost all studies on neoadjuvant EGFR-TKI treatment for EGFR-mutated NSCLC have been non-randomized controlled trials with small sample sizes and different methods of statistical analysis, which may lead to a lack of valid metrics to assess the feasibility and safety of neoadjuvant EGFR-TKI treatment. This meta-analysis aimed to assess the efficacy and safety of neoadjuvant EGFR-TKI treatment for NSCLC patients with EGFR mutations. METHODS: Relevant studies were systematically searched in PubMed, Embase, and Web of Science databases. Results including objective response rate (ORR), complete resection rate (R0), downstaging rate, pathological complete response (PCR), major pathological response (MPR), progression-free survival (PFS), overall survival (OS), and adverse events (AEs) were used for further analysis. RESULTS: This meta-analysis ultimately included 11 studies involving 344 patients with EGFR-positive mutations in NSCLC. In terms of tumor response, the pooled ORR was 57% (95% CI: 42%-73%), and in the Osimertinib subgroup, the pooled ORR was 80% (95% CI: 63%-98%). Analysis of studies that reported a downstaging rate showed the pooled downstaging rate of 41% (95% CI: 9%-74%) and the pooled downstaging rate of 74% (95% CI: 22%-100%) in the Osimertinib subgroup. In terms of surgical outcomes, the pooled pCR rate was 3% (95% CI: 0%-7%), the pooled MPR rate was 11% (95% CI: 6%-17%), and the pooled R0 resection rate was 91% (95% CI: 85%-95%). The most common adverse events associated with neoadjuvant therapy were rash and diarrhea. The pooled incidence of any grade of rash was 47.1% (95% CI: 25.4%-69.3%), and the pooled incidence of grade ≥ 3 rash was 0.6% (95% CI: 0.0%-2.5%). The pooled incidence of diarrhea of any grade was 28.8% (95% CI: 14.4%-45.4%), with the pooled incidence of grade ≥ 3 diarrhea of 0.2% (95% CI: 0.0%-1.6%). The pooled incidence of ≥ grade 3 adverse events was significantly lower. CONCLUSIONS: Our meta-analysis confirmed the efficacy and safety of neoadjuvant EGFR-TKIs for the treatment of NSCLC patients with EGFR-positive mutations and that third-generation EGFR-TKIs were superior to first- and second-generation EGFR-TKIs in terms of shrinking tumor volume and lowering tumor stage; however, future large-scale and multicenter randomized controlled trials are needed to confirm this conclusion. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42023466731.

Hypoxia-mediated promotion of glucose metabolism in non-small cell lung cancer correlates with activation of the EZH2/FBXL7/PFKFB4 axis.

F-box/LRR-repeat protein 7 (FBXL7) was predicted as a differentially expressed E3 ubiquitin ligase in non-small cell lung cancer (NSCLC), which has been suggested to influence cancer growth and metastasis. In this study, we aimed to decipher the function of FBXL7 in NSCLC and delineate the upstream and downstream mechanisms. FBXL7 expression was verified in NSCLC cell lines and GEPIA-based tissue samples, after which the upstream transcription factor of FBXL7 was bioinformatically identified. The substrate PFKFB4 of the FBXL7 was screened out by tandem affinity purification coupled with mass-spectrometry (TAP/MS). FBXL7 was downregulated in NSCLC cell lines and tissue samples. FBXL7 ubiquitinated and degraded PFKFB4, thus suppressing glucose metabolism and malignant phenotypes of NSCLC cells. Hypoxia-induced HIF-1α upregulation elevated EZH2 and inhibited FBXL7 transcription and reduced its expression, thus promoting PFKFB4 protein stability. By this mechanism, glucose metabolism and the malignant phenotype were enhanced. In addition, knockdown of EZH2 impeded tumor growth through the FBXL7/PFKFB4 axis. In conclusion, our work reveals that the EZH2/FBXL7/PFKFB4 axis plays a regulatory role in glucose metabolism and tumor growth of NSCLC, which is expected to be potential biomarkers for NSCLC.

N-Myc transcriptionally activates Skp2 to suppress p27 expression in small cell lung cancer.

BACKGROUND: Small cell lung cancer (SCLC) is characterized by a high proliferative rate, a strong predilection for early metastasis and poor prognosis. Novel SCLC biomarkers are urgently required to improve current diagnostic and treatment modalities. MYCN encodes the proto-oncogene N-Myc that is overexpressed in SCLC, but its downstream effectors are poorly characterized. Here, we investigated the role of the N-Myc/Skp2/p27 axis during SCLC progression. METHODS: Immunohistochemistry (IHC) and western blotting were performed to evaluate N-Myc/Skp2/p27 expression. SCLC cell apoptosis was investigated through TUNEL staining. Wound healing and transwell assays were performed to detect the migratory and invasive potential of SCLC cells. N-Myc and Skp2 binding was confirmed through luciferase reporter and ChIP assays. Xenograft models were developed to investigate the function of Skp2 during SCLC tumor growth in vivo. RESULTS: N-Myc and Skp2 were overexpressed in SCLC, whilst p27 expression was suppressed. Skp2 facilitated SCLC progression by protecting cells from apoptosis and facilitating cell migration and invasion. N-Myc was found to bind to the promoter region of Skp2 to enhance its expression. Skp2 enhanced tumor growth in vivo through the suppression of p27. Skp2 silencing reversed the pro-oncogenic effects of N-myc in SCLC tumors. CONCLUSION: We show that N-Myc enhances Skp2 to regulate p27 expression during SCLC progression. We therefore highlight the N-Myc/Skp2/p27 axis as a novel diagnostic and much-needed therapeutic target in SCLC.

Heat shock protein 47 promotes cell migration and invasion through AKT signal in non-small cell lung cancer.

Lung cancer is one of the most lethal malignancies, with the highest number of cases and deaths. Non-small cell lung cancer (NSCLC) is the most ordinary type of pathology in lung cancer. Meanwhile, various researchers have reported that heat shock protein 47 (HSP47) plays a vital regulatory role in cancer. However, the role of HSP47 in NSCLC is not clear. Consequently, the current study set out to investigate the role of HSP47 in the pathogenesis of NSCLC. First, we evaluated the expression patterns of HSP47 in NSCLC cell lines related to human normal lung epithelial cells, and HSP47 was found to be highly expressed in NSCLC cell lines. In addition, inhibiting the expression of HSP47 brought about marked repression in cell proliferation, migration and invasion in PC-9 cells. On the contrary, cell proliferation, migration and invasion were all elevated after over-expression of HSP47. Mechanistical experimentation further illustrated that protein kinase B (AKT) signal was repressed after inhibition of HSP47, and the influence of sh-HSP47 on cell proliferation, migration and invasion was countered by epidermal growth factor. Lastly, in-vivo animal models demonstrated that inhibition of HSP47 repressed cell tumorigenesis and AKT signal. Collectively, our findings illustrated that HSP47 was highly expressed in NSCLC cell lines, whereas inhibition of HSP47 repressed cell migration and invasion by diminishing the AKT signal. Inhibition of HSP47 also exhibited strong therapeutic effects on NSCLC in vivo.

Targeted Inhibition of the E3 Ligase SCFSkp2/Cks1 Has Antitumor Activity in RB1-Deficient Human and Mouse Small-Cell Lung Cancer.

The RB1 tumor suppressor gene is mutated in highly aggressive tumors including small-cell lung cancer (SCLC), where its loss, along with TP53, is required and sufficient for tumorigenesis. While RB1-mutant cells fail to arrest at G1-S in response to cell-cycle restriction point signals, this information has not led to effective strategies to treat RB1-deficient tumors, as it is challenging to develop targeted drugs for tumors that are driven by the loss of gene function. Our group previously identified Skp2, a substrate recruiting subunit of the SCF-Skp2 E3 ubiquitin ligase, as an early repression target of pRb whose knockout blocked tumorigenesis in Rb1-deficient prostate and pituitary tumors. Here we used genetic mouse models to demonstrate that deletion of Skp2 completely blocked the formation of SCLC in Rb1/Trp53-knockout mice (RP mice). Skp2 KO caused an increased accumulation of the Skp2-degradation target p27, a cyclin-dependent kinase inhibitor, which was confirmed as the mechanism of protection by using knock-in of a mutant p27 that was unable to bind to Skp2. Building on the observed synthetic lethality between Rb1 and Skp2, we found that small molecules that bind/inhibit Skp2 have in vivo antitumor activity in mouse tumors and human patient-derived xenograft models of SCLC. Using genetic and pharmacologic approaches, antitumor activity was seen with Skp2 loss or inhibition in established SCLC primary lung tumors, in liver metastases, and in chemotherapy-resistant tumors. Our data highlight a downstream actionable target in RB1-deficient cancers, for which there are currently no targeted therapies available. SIGNIFICANCE: There are no effective therapies for SCLC. The identification of an actionable target downstream of RB1, inactivated in SCLC and other advanced tumors, could have a broad impact on its treatment.

Prenatal influenza vaccination rescues impairments of social behavior and lamination in a mouse model of autism.

BACKGROUND: Prenatal infection is a substantial risk factor for neurodevelopmental disorders such as autism in offspring. We have previously reported that influenza vaccination (VAC) during early pregnancy contributes to neurogenesis and behavioral function in offspring. RESULTS: Here, we probe the efficacy of VAC pretreatment on autism-like behaviors in a lipopolysaccharide (LPS)-induced maternal immune activation (MIA) mouse model. We show that VAC improves abnormal fetal brain cytoarchitecture and lamination, an effect associated with promotion of intermediate progenitor cell differentiation in MIA fetal brain. These beneficial effects are sufficient to prevent social deficits in adult MIA offspring. Furthermore, whole-genome analysis suggests a strong interaction between Ikzf1 (IKAROS family zinc-finger 1) and neuronal differentiation. Intriguingly, VAC rescues excessive microglial Ikzf1 expression and attenuates microglial inflammatory responses in the MIA fetal brain. CONCLUSIONS: Our study implies that a preprocessed influenza vaccination prevents maternal bacterial infection from causing neocortical lamination impairments and autism-related behaviors in offspring.

Immunopotentiator Thymosin Alpha-1 Promotes Neurogenesis and Cognition in the Developing Mouse via a Systemic Th1 Bias.

In early life, the immune system plays an essential role in brain development. In our study, the immunopotentiator thymosin alpha-1 (Ta1) was peripherally administered to neonatal mice to explore whether the peripheral immunopotentiator affects neurodevelopment and cognition, and to further investigate the relevant mechanism. Compared with the control group, the Ta1 mice displayed better cognitive abilities in early life. The numbers of 5-bromodeoxyuridine (BrdU)+, nestin+, T-box transcription factor 2 (Tbr2)+, BrdU+/doublecortin (DCX)+, BrdU+/ionized calcium-binding adaptor molecule 1 (Iba1)+, and BrdU+/neuronal nuclei (NeuN)+ cells in the hippocampus were increased in the Ta1 group, accompanied by increased interleukin-4 (IL-4), interferon-gamma, brain-derived neurotrophic factor, nerve growth factor, and insulin-like growth factor-1 as well as decreased IL-6 and tumor necrosis factor-α. Furthermore, the Ta1-group showed a Th1-polarized immune response, and the neurotrophic factors were positively associated with the Th1/Th2 ratio. More importantly, administration of Ta1 blocked lipopolysaccharide-induced impairment of hippocampal neurogenesis in early life. These findings suggest that peripheral Ta1 contributes to neurogenesis and cognition probably through a systemic Th1 bias, as well as neuroprotection against LPS infection by Ta1.

Combined effect of BCG vaccination and enriched environment promote neurogenesis and spatial cognition via a shift in meningeal macrophage M2 polarization.

BACKGROUND: The spatial learning abilities of developing mice benefit from extrinsic cues, such as an enriched environment, with concomitant enhancement in cognitive functions. Interestingly, such enhancements can be further increased through intrinsic Bacillus Calmette-Guérin (BCG) vaccination. RESULTS: Here, we first report that combined neonatal BCG vaccination and exposure to an enriched environment (Enr) induced combined neurobeneficial effects, including hippocampal long-term potentiation, and increased neurogenesis and spatial learning and memory, in mice exposed to the Enr and vaccinated with BCG relative to those in the Enr that did not receive BCG vaccination. Neonatal BCG vaccination markedly induced anti-inflammatory meningeal macrophage polarization both in regular and Enr breeding mice. The meninges are composed of the pia mater, dura mater, and choroid plexus. Alternatively, this anti-inflammatory activity of the meninges occurred simultaneously with increased expression of the neurotrophic factors BDNF/IGF-1 and the M2 microglial phenotype in the hippocampus. Our results reveal a critical role for BCG vaccination in the regulation of neurogenesis and spatial cognition through meningeal macrophage M2 polarization and neurotrophic factor expression; these effects were completely or partially prevented by minocycline or anti-IL-10 antibody treatment, respectively. CONCLUSIONS: Together, we first claim that immunological factor and environmental factor induce a combined effect on neurogenesis and cognition via a common pathway-meningeal macrophage M2 polarization. We also present a novel functional association between peripheral T lymphocytes and meningeal macrophages after evoking adaptive immune responses in the periphery whereby T lymphocytes are recruited to the meninges in response to systemic IFN-γ signaling. This leads to meningeal macrophage M2 polarization, subsequent to microglial M2 activation and neurotrophic factor expression, and eventually promotes a positive behavior.

Neonatal hepatitis B vaccination impaired the behavior and neurogenesis of mice transiently in early adulthood.

The immune system plays a vital role in brain development. The hepatitis B vaccine (HBV) is administered to more than 70% of neonates worldwide. Whether this neonatal vaccination affects brain development is unknown. Newborn C57BL/6 mice were injected intraperitoneally with HBV or phosphate-buffered saline. HBV induced impaired behavioral performances and hippocampal long-term potentiation at 8 weeks (w) of age without influence at 4 or 12w. At 6w, there was decreased neurogenesis, M1 microglial activation and a neurotoxic profile of neuroimmune molecule expression [increased tumor necrosis factor-α and reduced interferon (IFN)-γ, brain-derived neurotrophic factor and insulin-like growth factor-1] in the hippocampus of the HBV-vaccinated mice. In the serum, HBV induced significantly higher levels of interleukin (IL)-4, indicating a T helper (Th)-2 bias. Moreover, the serum IFN-γ/IL-4 ratio was positively correlated with the levels of neurotrophins and neurogenesis in the hippocampus at the individual level. These findings suggest that neonatal HBV vaccination of mice results in neurobehavioral impairments in early adulthood by inducing a proinflammatory and low neurotrophic milieu in the hippocampus, which follows the HBV-induced systemic Th2 bias.

Neonatal BCG vaccination of mice improves neurogenesis and behavior in early life.

Bacillus Calmette-Guérin (BCG) is administered to neonates worldwide, but it is still unknown whether this neonatal vaccination affects brain development during early postnatal life, despite the close association of the immune system with the brain. Newborn C57BL/6 mice were injected subcutaneously with BCG or phosphate-buffered saline (PBS) and their mood status and spatial cognition were observed at four and eight weeks (w) old. The mice were also subjected to tests at 2 and 6 w to examine BCG's effects on neurogenesis, the hippocampal microglia phenotype and number, and the expression of hippocampal neuroimmune molecules and peripheral cytokines. The BCG-injected mice showed better behavioral performances at 4 w. We observed elevated neurogenesis, M2 microglial activation and a neurotrophic profile of neuroimmune molecules [more interferon (IFN)-γ, interleukin (IL)-4, transforming growth factor (TGF)-ß, brain-derived neurotrophic factor (BDNF) and insulin-like growth factor (IGF)-1 and less tumor necrosis factor (TNF)-α and IL-1ß] in the hippocampus of the 2-w-old BCG-mice. In the periphery, BCG induced a T helper (Th)-1 serum response. At the individual level, there were positive correlations between the serum IFN-γ/IL-4 ratio and the levels of neurotrophins and neurogenesis in the hippocampus. These findings suggest that neonatal BCG vaccination improved neurogenesis and mouse behavior in early life by affecting the neuroimmune milieu in the brain, which may be associated with a systemic Th1 bias.

Influenza A(H1N1) vaccination during early pregnancy transiently promotes hippocampal neurogenesis and working memory. Involvement of Th1/Th2 balance.

The 2009 influenza A(H1N1) pandemic led to a particularly high risk of morbidity and mortality among pregnant women. Therefore, inactivated influenza vaccines have been widely recommended for women in any period of gestation. Recent studies have shown that the peripheral adaptive immune system plays an important role in the function of the central nervous system (CNS). The present study was conducted to explore if influenza vaccination, aiming to induce protective immune activation, affects maternal neurogenesis and cognitive ability. The results showed that A(H1N1) pregnant mice (AIV+Pre) had superior spatial working memory performance compared with pregnant controls (Pre). At the cellular level, a transient increase in both cell proliferation and neuronal differentiation in the dentate gyrus (DG) was found in the AIV+Pre group compared with the Pre group when BrdU was injected on gestational day 14 (G14). However, there were no obvious differences between A(H1N1) virgin mice (AIV+Vir) and virgin controls (Vir) in both hippocampal neurogenesis and working memory. Our findings further indicated that prolactin (PRL) concentrations were not overtly different between the AIV+Pre group and the Pre group at any time. Interestingly, IL-4 and IFN-γ levels were obviously increased both in the serum and hippocampus of the AIV+Pre group (with a T helper-1 like response; Th1) compared with the Pre group (with a T helper-2 like response; Th2) at G14, whereas the expression of IL-6 and TNF-α, the proinflammatory factors, was significantly reduced. Altogether, the results suggest that A(H1N1) vaccination during early pregnancy may contribute to adult hippocampal neurogenesis and spatial working memory and that the improvements were, at least in part, associated with Th1/Th2 balance.

Glatiramer acetate reverses cognitive deficits from cranial-irradiated rat by inducing hippocampal neurogenesis.

Patients received cranial-irradiation can be affected with cognitive deficits and decreasing hippocampal neurogenesis. In this work, we characterized the cognitive ability and immune-induced neurogenesis of the pre- and post-treated cranial-irradiated rats with Glatiramer acetate (GA), known as a weak CNS auto-antigen. The GA-treated rats displayed better cognitive abilities in Morris water maze (MWM). The numbers of Iba-I-positive microglia, BrdU(+)/DCX(+) cells and BrdU(+)/NeuN(+) cells in hippocampus increased, which are accompanied with increased IFN-γ and decreased IL-6, IL-4. Furthermore, GA reverted the Th1/Th2 balance. GA treatment can reverse the cognitive deficits caused by cranial irradiation through a mechanism that likely involves immunomodulation.

Short amyloid-ß immunogens with spacer-enhanced immunogenicity without junctional epitopes for Alzheimer's disease immunotherapy.

Induction of an immune response to amyloid-ß (Aß) protein is effective in treating animal models of Alzheimer's disease. The Aß1-15 sequence contains the antibody epitope(s), but lacks the T-cell reactive sites of full-length Aß1-42. We tested two alternative peptide immunogens encompassing either a tandem repeat of GPGPG-linked Aß1-15 sequences (2Aß15-linker) or a tandem repeat Aß1-15 without the spacer sequence (2Aß15). Titers of the immunized sera were measured by indirect ELISA. We analyzed the production of interferon-γ and interleukin-4 cytokine by lymphocytes and CD4 T-cells using ELISPOT and FACS assays; we then measured CD4 T-cell proliferation using a CFSE-based lymphoproliferation assay. Immunization with 2Aß15-linker resulted in a high anti-Aß titer of the noninflammatory T-helper 2 isotype, a lack of lymphocyte proliferation against the spacer part peptide. We observed much lower titers against the Aß protein after immunization with 2Aß15. Restimulation of lymphocytes with the corresponding immunogens resulted in proliferative responses, which showed that the sequential arrangement of the epitopes created junctional epitopes. The disruption of junctional epitopes through the introduction of a GPGPG spacer restored the immunogenicity against all the epitopes. Our novel immunogen with spacer may be a safer alternative to a peptide-based vaccine.

Bilobalide regulates soluble amyloid precursor protein release via phosphatidyl inositol 3 kinase-dependent pathway.

Bilobalide (BB) is a sesquiterpenoid extracted from Ginkgo biloba leaves. An increasing number of studies have demonstrated its neuroprotective effects. The neuroprotective mechanisms may be associated with modulation of intracellular signaling cascades such as the phosphatidyl inositol 3-kinase (PI3K) pathway. Using differentiated SH-SY5Y cells, this study investigated whether BB modulation of intracellular signaling pathways, such as the protein kinase C (PKC) and PI3K pathways, contributes to amyloid precursor protein (APP) metabolism, a key event in the pathogenesis of Alzheimer's disease (AD). We demonstrated in this study that BB enhanced the secretion of α-secretase-cleaved soluble amyloid precursor protein (sAPPα, a by-product of non-amyloidogenic processing of APP) and decreased the ß amyloid protein (Aß, a by-product of amyloidogenic processing of APP) via PI3K-dependent pathway. The PI3K pathway mediated the rapid effect of BB on APP processing possibly via regulation of intracellular APP trafficking. After longer time BB incubation (12h), this effect was reinforced by PI3K pathway-mediated up-regulation of disintegrin and metalloproteinase domain-containing protein 10 (ADAM10, an α-secretase candidate). Given the strong association between APP metabolism and AD pathogenesis, the ability of BB to regulate APP processing suggests its potential use in AD prevention.

Bilobalide protects mitochondrial function in ovariectomized rats by up-regulation of mRNA and protein expression of cytochrome c oxidase subunit I.

Bilobalide (BB), a sesquiterpene trilactone from Ginkgo biloba has been proposed to have protective effects on mitochondrial function. Using ovariectomized rats to mimic the post-menopausal pathophysiological changes in women, this study demonstrated that BB treatment could prevent estrogen withdrawal-induced decrease in mitochondrial adenosine triphosphate content, cytochrome c oxidase subunit I (COXI) mRNA and protein levels and COX activity in hippocampal tissues as effectively as estradiol benzoate. But neither ovariectomy nor BB treatment affected citrate synthase activity. These results suggested that BB was able to regulate COX activity via up-regulation of the gene and protein expression of its mitochondrial DNA-coded subunits, and modulation of COX activity by BB might contribute to its protective effects on mitochondrial function. Given that ovariectomy induces decrease in estrogen levels similar to that of menopause, BB may be useful in developing therapy for neurodegenerative diseases such as Alzheimer's disease in post-menopausal females.

Tetravalent Abeta1-15 vaccine reduces TCR-positive cell infiltration and up-regulates p75 in Tg2576 brains compared to Abeta42 vaccine.

In order to investigate the effect of Abeta vaccines on T cell infiltration into the brain, we immunized Tg2576 mice with two adenovirus vaccines containing tetravalent Abeta1-15 (4xAbeta15) or Abeta42. TCR-positive cells were found in the ventricle, parenchyma, and surrounding the vasculature, especially concentrating in the periventricular parenchyma, the reticular part of the substantia nigra and the corpus striatum. Compared to the Abeta42 group, TCR-positive cells in the tetravalent (4x) Abeta15 group were significantly decreased. Both vaccines down-regulated neurotrophic and inflammatory factors, but the 4xAbeta15 vaccine up-regulated TrkA and p75 compared with the Abeta42 vaccine. The results suggest that the 4xAbeta15 vaccine might be safer and more beneficial than the Abeta42 vaccine.

Inhibition of human prostate cancer xenograft growth by 125I labeled triple-helix forming oligonucleotide directed against androgen receptor.

BACKGROUND: The failure of hormone treatment for advanced prostate cancer might be related to aberrant activation of the androgen receptor. We have shown that (125)I labeled triple-helix forming oligonucleotide (TFO) against the androgen receptor gene inhibits androgen receptor expression and cell proliferation of LNCaP prostate cancer cells in vitro. This study aimed at exploring the effects of the (125)I-TFO on prostate tumor growth in vivo using a nude mouse xenograft model. METHODS: TFO was labeled with (125)I by the iodogen method. Thirty-two nude mice bearing LNCaP xenograft tumors were randomized into 4 groups and were intratumorally injected with (125)I-TFO, unlabeled TFO, Na(125)I and normal saline. Tumor size was measured weekly. The tumor growth inhibition rate (RI) was calculated by measurement of tumor weight. The expression of the androgen receptor gene was performed by RT-PCR and immunohistochemical study. The prostate specific antigen (PSA) serum levels were measured by enzyme linked immunosorbent assay. The tumor cell apoptosis index (AI) was detected by TUNEL assay. RESULTS: Tumor measurements showed that tumor development was significantly inhibited by either (125)I-TFO or TFO, with tumor RIs of 50.79% and 32.80% respectively. (125)I-TFO caused greater inhibition of androgen receptor expression and higher AIs in tumor tissue than TFO. Both the tumor weight and the PSA serum levels in (125)I-TFO treated mice ((0.93 +/- 0.15) g and (17.43 +/- 1.85) ng/ml, respectively) were significantly lower than those ((1.27 +/- 0.21) g and (28.25 +/- 3.41) ng/ml, respectively) in TFO treated mice (all P < 0.05). Na(125)I did not significantly affect tumor growth and androgen receptor expression in tumor tissue. CONCLUSIONS: The (125)I-TFO can effectively inhibit androgen receptor expression and tumor growth of human prostate cancer xenografts in vivo. The inhibitory efficacy of (125)I-TFO is more potent than that of TFO, providing a reference for future studies of antigen radiotherapy.

Vaccination of Alzheimer's model mice with adenovirus vector containing quadrivalent foldable Abeta(1-15) reduces Abeta burden and behavioral impairment without Abeta-specific T cell response.

Active amyloid beta (Abeta) vaccination has been shown to be effective in clearing cerebral Abeta and improving cognitive function in mouse models of Alzheimer's disease (AD). The meningoencephalitis observed in AD vaccination trial was likely related to excessive T cell-mediated immunity caused by the immunogen Abeta(1-42). To avoid this toxicity, previous researchers have been using synthetic truncated Abeta derivatives that promote humoral immunity. In this study, we develop a novel adenovirus vaccine, which can express quadrivalent foldable Abeta(1-15) (4 x Abeta(15)) and gene adjuvant GM-CSF in vivo. Importantly, the 4 x Abeta(15) sequence includes an Abeta-specific B cell epitope but lacks the reported T cell epitope. The 4 x Abeta(15) adenovirus vaccine induces an Abeta-specific IgG1 predominant humoral immune response, and reduces brain Abeta deposition and cognition deficits in Tg2576 mice. Detection of IL-4 and IFN-gamma in restimulated splenocytes shows a significant Th2-polarized immune response. Stimulation of splenocytes with 4 x Abeta(15) peptides results in robust proliferative responses, whereas proliferation is absent after stimulation with full-length Abeta, which indicates that the 4 x Abeta(15) adenovirus vaccine does not induce Abeta-specific T cellular immune response. Thus, our results raise the possibility that adenovirus vector encoding 4 x Abeta(15) would be a promising candidate for future AD vaccination program.