Photo-Activated Oxidative Stress Amplifier: A Strategy for Targeting Glutathione Metabolism and Enhancing ROS-Mediated Therapy in Triple-Negative Breast Cancer Treatment.

Amplifying oxidative stress within tumor cells can effectively inhibit the growth and metastasis of triple-negative breast cancer (TNBC). Therefore, the development of innovative nanomedicines that can effectively disrupt the redox balance represents a promising yet challenging therapeutic strategy for TNBC. In this study, an oxidative stress amplifier, denoted as PBCH, comprising PdAg mesoporous nanozyme and a CaP mineralized layer, loaded with GSH inhibitor L-buthionine sulfoximine (BSO), and further surface-modified with hyaluronic acid that can target CD44, is introduced. In the acidic tumor microenvironment, Ca2+ is initially released, thereby leading to mitochondrial dysfunction and eventually triggering apoptosis. Additionally, BSO suppresses the synthesis of intracellular reduced GSH and further amplifies the level of oxidative stress in cancer cells. Furthermore, PdAg nanozyme can be activated by near-infrared light to induce photothermal and photodynamic effects, causing a burst of ROS and simultaneously promoting cell apoptosis via provoking immunogenic cell death. The high-performance therapeutic effects of PBCH, based on the synergistic effect of aforementioned multiple oxidative damage and photothermal ablation, are validated in TNBC cells and animal models, declaring its potential as a safe and effective anti-tumor agent. The proposed approach offers new perspectives for precise and efficient treatment of TNBC.

New advances in the treatment of chondrosarcoma under the PD-1/PD-L1 pathway.

ABSTRACT: Bone sarcomas encompass a group of spontaneous mesenchymal malignancies, among which osteosarcoma, Ewing sarcoma, chondrosarcoma, and chordoma are the most common subtypes. Chondrosarcoma, a relatively prevalent malignant bone tumor that originates from chondrocytes, is characterized by endogenous cartilage ossification within the tumor tissue. Despite the use of aggressive treatment approaches involving extensive surgical resection, chemotherapy, and radiotherapy for patients with osteosarcoma, chondrosarcoma, and chordoma, limited improvements in patient outcomes have been observed. Furthermore, resistance to chemotherapy and radiation therapy has been observed in chondrosarcoma and chordoma cases. Consequently, novel therapeutic approaches for bone sarcomas, including chondrosarcoma, need to be uncovered. Recently, the emergence of immunotherapy and immune checkpoint inhibitors has garnered attention given their clinical success in various diverse types of cancer, thereby prompting investigations into their potential for managing chondrosarcoma. Considering that circumvention of immune surveillance is considered a key factor in the malignant progression of tumors and that immune checkpoints play an important role in modulating antitumor immune effects, blockers or inhibitors targeting these immune checkpoints have become effective therapeutic tools for patients with tumors. One such checkpoint receptor implicated in this process is programmed cell death protein-1 (PD-1). The association between PD-1 and programmed cell death ligand-1 (PD-L1) and cancer progression in humans has been extensively studied, highlighting their remarkable potential as biomarkers for cancer treatment. This review comprehensively examines available studies on current chondrosarcoma treatments and advancements in anti-PD-1/PD-L1 blockade therapy for chondrosarcoma.

A Multifunctional Bimetallic Nanoplatform for Synergic Local Hyperthermia and Chemotherapy Targeting HER2-Positive Breast Cancer.

Anti-HER2 (human epidermal growth factor receptor 2) therapies significantly increase the overall survival of patients with HER2-positive breast cancer. Unfortunately, a large fraction of patients may develop primary or acquired resistance. Further, a multidrug combination used to prevent this in the clinic places a significant burden on patients. To address this issue, this work develops a nanotherapeutic platform that incorporates bimetallic gold-silver hollow nanoshells (AuAg HNSs) with exceptional near-infrared (NIR) absorption capability, the small-molecule tyrosine kinase inhibitor pyrotinib (PYR), and Herceptin (HCT). This platform realizes targeted delivery of multiple therapeutic effects, including chemo-and photothermal activities, oxidative stress, and immune response. In vitro assays reveal that the HCT-modified nanoparticles exhibit specific recognition ability and effective internalization by cells. The released PYR inhibit cell proliferation by downregulating HER2 and its associated pathways. NIR laser application induces a photothermal effect and tumor cell apoptosis, whereas an intracellular reactive oxygen species burst amplifies oxidative stress and triggers cancer cell ferroptosis. Importantly, this multimodal therapy also promotes the upregulation of genes related to TNF and NF-κB signaling pathways, enhancing immune activation and immunogenic cell death. In vivo studies confirm a significant reduction in tumor volume after treatment, substantiating the potential effectiveness of these nanocarriers.

Intra-Anterior Chamber Injection of Ranibizumab in Advanced Pediatric Vitreoretinal Diseases.

Importance: Anti-vascular endothelial growth factor (VEGF) treatment through intravitreal or subretinal administrations has been proven effective for VEGF-driven pediatric vitreoretinal diseases but are not feasible for advanced cases, such as shallow traction retinal detachments or peripheral circumferential retinal detachments which adhere to the lens. Intra-anterior chamber injection (IAcI) of anti-VEGF may be a viable alternative in such cases but needs evaluation. Objective: To investigate the effects and safety of IAcI of anti-VEGF to treat VEGF-driven pediatric vitreoretinal diseases. Design, Setting, and Participants: This was a retrospective observational case series study conducted at Xinhua Hospital, affiliated with Shanghai Jiao Tong University School of Medicine in China. The study included 14 eyes of 13 children diagnosed with vitreoretinal disease exhibiting elevated vascular activity between January and August 2023. Intervention: IAcI with ranibizumab. Main Outcomes and Measures: Retinal vascular abnormalities, vitreous hemorrhage resolution, and complications 1 month and 3 months after injection. Results: Of 13 patients included in this study, 12 were male. The mean age was 4.6 years (range, 1 month to 9 years). Six patients were diagnosed with familial exudative vitreoretinopathy, 4 with morning glory syndrome, 1 with retinopathy of prematurity, and 2 with chronic retinal detachments of unknown causes. At 1-month postoperative follow-up, vascular activity had decreased in 14 of 14 eyes. At 3-month follow-up, vascular activity had resolved in 7 of 14 eyes, persisted in 6 of 14 eyes, and reactivated in 1 of 14 eyes. On final observation, no complications were reported. Conclusions and Relevance: These findings support the possibility of treatment using IAcI with ranibizumab to decrease retinal vascular abnormalities in familial exudative vitreoretinopathy or retinopathy of prematurity or related conditions, but further studies are needed to understand more precise benefits and risks. This approach might be considered in cases where intravitreal or subretinal injection are not feasible, recognizing the limitations of these findings and that longer-term outcomes still need to be monitored.

RNA-seq analysis reveals candidate genes associated with proliferation, invasion, and migration in BCL11A knockdown B-NHL cell lines.

B-cell lymphoma/leukemia 11A (BCL11A) is highly expressed in B-cell non-Hodgkin lymphoma (B-NHL), blocks cell differentiation, and inhibits cell apoptosis. However, little is known about BCL11A in the proliferation, invasion, and migration of B-NHL cells. Here, we found increased expression of BCL11A in B-NHL patients and cell lines. Knockdown of BCL11A suppressed the proliferation, invasion, and migration of B-NHL cells in vitro and reduced tumor growth in vivo. RNA sequencing (RNA-seq) and KEGG pathway analysis demonstrated that BCL11A-targeted genes were significantly enriched in the PI3K/AKT signaling pathway, focal adhesion, and extracellular matrix (ECM)-receptor interaction (including COL4A1, COL4A2, FN1, SPP1), and SPP1 was the most significantly downregulated gene. qRT‒PCR, western blotting, and immunohistochemistry revealed that silencing BCL11A reduced the expression level of SPP1 in Raji cells. Our study suggested that high level of BCL11A may promote B-NHL proliferation, invasion, and migration, and the BCL11A-SPP1 regulatory axis may play an important role in Burkitt's lymphoma.

Corrigendum: RAB42 promotes glioma pathogenesis via the VEGF signaling pathway.

[This corrects the article DOI: 10.3389/fonc.2021.657029.].

Higher Levels of Urinary Thiocyanate, a Biomarker of Cruciferous Vegetable Intake, Were Associated With Lower Risks of Cardiovascular Disease and All-Cause Mortality Among Non-smoking Subjects.

Background: Epidemiologic studies on cruciferous vegetable (CV) intake and cardiovascular disease (CVD) were inconclusive. Objective: To investigate the associations of urinary thiocyanate, a biomarker of CV intake, with CVD and all-cause mortality among non-smoking adults. Methods: This prospective cohort study comprised 10,489 non-smoking adults (weighted mean age, 46.8 years; 43.4% male) from the National Health and Nutrition Examination Survey 2001-2014. Non-smokers were defined as subjects with serum cotinine < 3 ng/mL. Urinary thiocyanate was measured with ion chromatography tandem mass spectrometry at baseline, and CVD and all-cause mortality were identified through linkage to National Death Index until December 31, 2015. Cox proportional hazards model was applied to estimate the hazard ratios (HRs) with 95% confidence intervals (CIs) for CVD and all-cause mortality. Results: A total of 800 deaths, of which 136 died of CVD, were ascertained within a median 7.8 years of follow-up. Urinary thiocyanate was positively correlated with total CV intake among non-smoking adults (r s = 0.088, P < 0.001). Comparing extreme quartiles, the multivariate-adjusted HRs for CVD and all-cause mortality were 0.50 (95% CI: 0.29-0.85) and 0.75 (95% CI: 0.60-0.92), respectively. Each 1 µg/g creatinine increment of log-transformed urinary thiocyanate was associated with a 25% (HR: 0.75; 95% CI: 0.62-0.91) reduced CVD mortality risk and 12% (HR: 0.88; 95% CI: 0.81-0.96) reduced all-cause mortality risk. The documented inverse associations persisted in sensitivity analyses. Conclusion: Increased levels of urinary thiocyanate, a candidate biomarker of CV intake, were associated with low risks of CVD and total mortality among non-smoking adults. This prospective biomarker-based study provided further evidence to support the cardiovascular benefits of CVs.

DHPPA, a major plasma alkylresorcinol metabolite reflecting whole-grain wheat and rye intake, and risk of metabolic syndrome: a case-control study.

PURPOSE: Whole-grain intake assessed through self-reported methods has been suggested to be inversely associated with the metabolic syndrome (MetS) risk in epidemiological studies. However, few studies have evaluated the association between whole-grain intake and MetS risk using objective biomarkers of whole-grain intake. The aim of this study was to examine the association between plasma 3-(3,5-Dihydroxyphenyl)-1-propanoic acid (DHPPA), a biomarker of whole-grain wheat and rye intake, and MetS risk in a Chinese population. METHODS: A case-control study of 667 MetS cases and 667 matched controls was conducted based on baseline data of the Tongji-Ezhou Cohort study. Plasma DHPPA concentrations were assessed by high-performance liquid chromatography-tandem mass spectrometry. The MetS was defined based on criteria set by the Joint Interim Statement. RESULTS: Plasma DHPPA was inversely associated with MetS risk. After adjustment for age, sex, body mass index, smoking status, alcohol drinking status, physical activity and education level, the odds ratios (ORs) for MetS across increasing quartiles of plasma DHPPA concentrations were 1 (referent), 0.86 (0.58-1.26), 0.77 (0.52-1.15), and 0.59 (0.39-0.89), respectively. In addition, the cubic spline analysis revealed a potential nonlinear association between plasma DHPPA and MetS, with a steep reduction in the risk at the lower range of plasma DHPPA concentration. CONCLUSION: Our study revealed that individuals with higher DHPPA concentrations in plasma had lower odds of MetS compared to those with lower DHPPA concentrations in plasma. Our findings provided further evidence to support health benefits of whole grain consumption.

Associations of Moderate Low-Carbohydrate Diets With Mortality Among Patients With Type 2 Diabetes: A Prospective Cohort Study.

CONTEXT: A statement of context for the abstract was added in Objective as follows: Lower-carbohydrate-diet (LCD) has been reported to have beneficial effects on cardiovascular risk factor profile in general population. However, whether adherence to an LCD could benefit long-term survival among individuals with diabetes is unclear. OBJECTIVE: This work aimed to investigate the associations of different types of lower-carbohydrate diets with mortality among individuals with type 2 diabetes (T2D). METHODS: This prospective study included 5677 patients with T2D. The overall, unhealthy, and healthy lower-carbohydrate-diet (LCD) scores were calculated based on the percentage of energy from total and subtypes of carbohydrate, protein, and fat. Deaths were determined via linkage to the National Death Index records until December 31, 2015. Cox proportional hazards models were used to estimate the hazard ratios (HRs) and 95% CIs of mortality. RESULTS: During a median of 6.3 years of follow-up (39 401 person-years), 1432 deaths were documented. After multivariable adjustment including lifestyle factors, diabetes duration, and glycated hemoglobin A1c, patients in the third quartile of overall LCD score had the lowest risk of mortality (HR: 0.65; 95% CI, 0.50-0.85), compared with the first quartile. The multivariable-adjusted HRs (95% CIs) of mortality across quartiles of healthy lower-carbohydrate-diet score were 1.00 (reference), 0.78 (0.64-0.96), 0.73 (0.58-0.91), and 0.74 (0.58-0.95) (Ptrend = .01). Isocalorically replacing 2% of energy from carbohydrates with plant-based protein or polyunsaturated fatty acids was associated with 23% to approximately 37% lower total mortality. Similar results were observed when analyses were stratified by age, sex, race/ethnicity, smoking status, body mass index, physical activity, and diabetes duration. CONCLUSION: Healthy LCD score was significantly associated with a lower risk of mortality in adults with T2D. Adherence to a well-balanced moderate lower-carbohydrate diet that emphasizes healthy carbohydrates, plant-based protein, and polyunsaturated fat may prevent premature death among patients with T2D.

Atrazine exposure and recovery alter the intestinal structure, bacterial composition and intestinal metabolites of male Pelophylax nigromaculatus.

The pesticide atrazine poses a potential threat to the health of frogs living in farmland areas. The exposure concentration in traditional pesticide experiments is usually constant, while pesticide pollution in actual water may fluctuate due to periodic or seasonal application. We examined the effects of different concentrations of atrazine (50, 100 and 500 µg/L) over a 14-day exposure and a 7-day recovery on intestinal histology, bacterial composition and intestinal metabolites of male Pelophylax nigromaculatus. HE staining revealed that after a 14-day atrazine exposure, the 100 µg/L and 500 µg/L groups showed obvious cysts and significantly decreased intestinal crypt depth and villus height. After a 7-day recovery, the damaged intestine in the 100 µg/L group was partially recovered, while in the 500 µg/L exposure group there was no improvement. 16S rRNA gene analysis of intestinal bacteria showed that 500 µg/L atrazine exposure significantly caused a persistent decrease in bacterial α diversity. Compared to the control and other atrazine exposure groups, the 500 µg/L group showed significant changes in the relative abundance of predominant bacteria. In addition, most dominant bacteria in the 500 µg/L recovery group showed significant differences with the 50 µg/L and 100 µg/L recovery groups. Nontargeted metabolomics profiling based on UPLC/MS analysis showed that atrazine exposure and recovery induced changes in the intestinal metabolic profile. The changes in metabolites were mainly related to purine/pyrimidine metabolism, glycine, serine and threonine metabolism, and arginine and proline metabolism. In general, these pathways were closely related to energy metabolism and amino acid metabolism. These results suggest that the short-term exposure to 500 µg/L atrazine causes persistent harm to intestinal health. This study is an important step toward a better understanding of the toxic effects of atrazine exposure and recovery in frog intestines.

RAB42 Promotes Glioma Pathogenesis via the VEGF Signaling Pathway.

Angiogenesis plays an important role in tumor initiation and progression of glioma. Seeking for biomarkers associated with angiogenesis is important in enhancing our understanding of glioma biologically and identifying its new drug targets. RNA-sequencing (RNA-seq) data and matched clinical data were downloaded from the CGGA database. A series of filtering analyses were performed to screen for reliable genes: survival, multivariate Cox, ROC curve filtration, and clinical correlation analyses. After immunohistochemical verification, RAB42 was identified as a reliable gene for further single gene analysis. Afterwards, we performed gene set enrichment analysis (GSEA) and co-expression analysis to establish the related molecular mechanisms and signal pathways in glioma. Finally, the gene functions and the mechanisms were investigated in vitro experiments. A total of 23270 mRNA expression and 1018 glioma samples were included in this study. After the three filtering analyses, we selected ten genes for immunohistochemical verification: KLHDC8A, IKIP, HIST1H2BK, HIST1H2BJ, GNG5, FAM114A1, TMEM71, RAB42, CCDC18, and GAS2L3. Immunostaining demonstrated that RAB42 was significantly expressed on the membrane of glioma tissues but not in normal tissues. These results were verified and validated in GEPIA datasets, and the association between RAB42 with clinical features was also evaluated. Analysis of gene functions indicated that RAB42 activated VEGF signaling pathways and the mechanism was associated with natural killer cell mediated cytotoxicity, JAK-STAT signaling pathway and apoptosis pathways by PI3K/AKT in gliomas. Experiments in vitro suggested that the proliferation and invasion of glioma cells might be inhibited after downregulating of RAB42. And the tumorigenesis promotion of RAB42 may relate to the activation of VEGF signaling pathway. Taken together, this study shows that the overexpression of RAB42 is an independent prognostic factor of adverse prognosis. Its pro-oncogenic mechanism may be associated with the activation of VEGF signaling pathways.

Association of Gut Microbiota-Dependent Metabolite Trimethylamine N-Oxide with First Ischemic Stroke.

AIM: We aimed to investigate the relationship of trimethylamine N-oxide (TMAO) concentrations with ischemic stroke in a large-scale case-control study conducted among the hospital-based general population. METHODS: We recruited 953 case-control sex- and age-matched pairs, and cases were confined to first acute ischemic stroke in this study. Fasting plasma TMAO was measured using high-performance liquid chromatography-tandem mass spectroscopy. Conditional logistic regression analysis was conducted to calculate odds ratios (OR) for the association of plasma TMAO with ischemic stroke. RESULTS: We found that plasma TMAO concentrations in patients with ischemic stroke were significantly higher than that in the control group (median: 2.85 µmol/L vs. 2.33 µmol/L, P＜0.001). In multivariable conditional logistic regression models, higher plasma TMAO concentrations were associated with increased odds of ischemic stroke [fully adjusted OR for highest vs. lowest TMAO quartile: 1.81; 95% confidence interval (CI): 1.27, 2.59; P for trend ＜0.001]. The multivariable-adjusted OR for ischemic stroke per 1 µmol/L increment of plasma TMAO was 1.05 (95% CI: 1.02, 1.08). Additionally, the positive association also persisted in subgroups stratified by age, sex, body mass index, smoking status, alcohol habits, history of diabetes, and history of hypertension. CONCLUSIONS: This study suggested a positive association between plasma TMAO and ischemic stroke. Further studies are required to explore the role of plasma TMAO concentrations in predicting stroke risk.

BCL11A: a potential diagnostic biomarker and therapeutic target in human diseases.

Transcription factor B-cell lymphoma/leukemia 11A (BCL11A) gene encodes a zinc-finger protein that is predominantly expressed in brain and hematopoietic tissue. BCL11A functions mainly as a transcriptional repressor that is crucial in brain, hematopoietic system development, as well as fetal-to-adult hemoglobin switching. The expression of this gene is regulated by microRNAs, transcription factors and genetic variations. A number of studies have recently shown that BCL11A is involved in ß-hemoglobinopathies, hematological malignancies, malignant solid tumors, 2p15-p16.1 microdeletion syndrome, and Type II diabetes. It has been suggested that BCL11A may be a potential prognostic biomarker and therapeutic target for some diseases. In this review, we summarize the current research state of BCL11A, including its biochemistry, expression, regulation, function, and its possible clinical application in human diseases.

Procyanidins Extracted from Lotus Seedpod Ameliorate Amyloid-ß-Induced Toxicity in Rat Pheochromocytoma Cells.

Alzheimer's disease (AD) is a progressive neurodegenerative disease, which is characterized by extracellular senile plaque deposits, intracellular neurofibrillary tangles, and neuronal apoptosis. Amyloid-ß (Aß) plays a critical role in AD that may cause oxidative stress and downregulation of CREB/BDNF signaling. Anti-Aß effect has been discussed as a potential therapeutic strategy for AD. This study aimed to identify the amelioration of procyanidins extracted from lotus seedpod (LSPC) on Aß-induced damage with associated pathways for AD treatment. Rat pheochromocytoma (PC12) cells incubated with Aß 25-35 serve as an Aß damage model to evaluate the effect of LSPC in vitro. Our findings illustrated that LSPC maintained the cellular morphology from deformation and reduced apoptosis rates of cells induced by Aß 25-35. The mechanisms of LSPC to protect cells from Aß-induced damage were based on its regulation of oxidation index and activation of CREB/BDNF signaling, including brain-derived neurotrophic factor (BDNF) and phosphorylation of cAMP-responsive element-binding (CREB), protein kinase B (also known as AKT), and the extracellular signal-regulated kinase (ERK). Of note, by high-performance liquid chromatography-tandem mass spectroscopy (LC-MS/MS), several metabolites were detected to accumulate in vivo, part of which could take primary responsibility for the amelioration of Aß-induced damage on PC12 cells. Taken together, our research elucidated the effect of LSPC on neuroprotection through anti-Aß, indicating it as a potential pretreatment for Alzheimer's disease.

Chinese and Europeans with acute myeloid leukemia have discordant mutation topographies.

Although the topography of mutations in persons of predominately European-descent with acute myeloid leukemia (AML) is well-described this is less so in Asians. We studied AML-related mutations in 289 consecutive Chinese (mostly Han) with newly-diagnosed de novo AML. Full-length coding sequence of NPM1 and CEBPA, IDH1 and IDH2 hotspot mutations and WT1 mutations in exons 7 and 9 were analyzed by PCR as were correlations with clinical and laboratory variables. CEBPA mutations were detected in 20% of subjects (95% confidence interval [CI] 15, 25%), NPM1 mutations in 20% (15, 25%), IDH1 mutations in 4% (1, 6%), IDH2 mutations in 11% (7, 15%) and WT1 mutations in 6% (3, 9%). A comparison of these data with mutation frequencies in persons of predominately European-descent with AML indicates a higher frequency of CEBPA mutations, a similar frequency of IDH2 mutations and lower frequencies of NPM1, IDH1 and WT1 mutations. Our data indicate different topographies of AML-associated mutations in Chinese compared with persons of predominately European descent suggesting genetic background, life-style, environment and perhaps other variables may influence these differences.

B7-H6 expression is induced by lipopolysaccharide and facilitates cancer invasion and metastasis in human gliomas.

Although great progress has been made in treatment regimens, gliomas are still incurable and the 5-year survival remains poor. Studies focusing on molecules that regulate tumorigenesis or tumor immunity may provide potential therapeutic strategies for patients with glioma. B7-H6 is selectively expressed in tumor cells and plays vital roles in host immune responses. In this study, we demonstrated that B7-H6 was expressed in glioma cell lines, including CRT, U251, SHG-44, SF-295, TG-905 and U373, and tumor tissues isolated from glioma patients. Moreover, the expression levels of B7-H6 were significantly correlated with glioma grade. Previous studies reported that inflammatory mediators and cytokines induced the expression of B7 family members including programmed death-ligand 1, B7-H2 and B7-H4. Therefore, we explored the regulation of B7-H6 expression in gliomas and showed that lipopolysaccharide induced the expression of B7-H6 in glioma cells. To further analyze the roles of B7-H6 in gliomas, the expression of B7-H6 in glioma cells was knocked down. The results of cell counting kit-8, colony formation, wound healing, and transwell migration and invasion assays demonstrated that the proliferation, migration and invasion of glioma cells were inhibited after knocking down B7-H6. To elucidate the specific mechanisms of B7-H6 function in cancer progression, we examined the expression levels of proteins involved in cell apoptosis, migration and invasion. We demonstrated that the expression levels of E-cadherin and Bcl-2 associated X protein increased, and the expression levels of vimentin, N-cadherin, matrix metalloproteinase-2, matrix metalloproteinase-9 and survivin decreased after knocking down B7-H6. In conclusion, B7-H6 plays important roles in glioma, and targeting B7-H6 may provide a novel therapeutic strategy for glioma patients.

TLR4 interaction with LPS in glioma CD133+ cancer stem cells induces cell proliferation, resistance to chemotherapy and evasion from cytotoxic T lymphocyte-induced cytolysis.

Despite advances in treatment modalities, 5-year survival among glioma patients remains poor. Glioma cancer stem cells (CSCs) exhibit high tumorigenic activity and are associated with resistance to treatment and tumor recurrence. Because overexpression of toll-like receptor 4 (TLR4) correlated with cancer development, we investigated LPS-induced TLR4 signaling in glioma CD133-positive (CD133+) CSCs. The proliferation of CD133+ CSCs isolated from CSCs derived from the U251 and SF295 glioma cell lines and from human glioma samples was upregulated on a time- and concentration-dependent basis by LPS stimulation, with increases in CD133, NANOG, and NESTIN mRNA and protein levels. Also elevated was cytokine expression, which was coupled to phosphorylation of mitogen-activated protein kinase, and activation of cyclins and cyclin-dependent kinase complexes. TLR4 knockdown reduced LPS-induced CD133+ CSC proliferation, whereas Adriamycin-induced CD133+ CSC apoptosis was moderately inhibited by treatment with LPS, implying a protective effect of LPS. The capacity of glioma CD133+ CSC-reactive cytotoxic T lymphocyte to selectively kill CD133+ CSCs was reduced by LPS, and this effect was not apparent after TLR4 knockdown in CD133+ CSCs. These data suggest TLR4 signaling is a factor in CD133+ CSC immune evasion, and thus disruption of TLR4 signaling is a potential therapeutic strategy in glioma.

BCL11A expression in acute phase chronic myeloid leukemia.

Chronic myeloid leukemia (CML) has chronic and acute phases. In chronic phase myeloid differentiation is preserved whereas in acute phase myeloid differentiation is blocked. Acute phase CML resembles acute myeloid leukemia (AML). Chronic phase CML is caused by BCR-ABL1. What additional mutation(s) cause transition to acute phase is unknown and may differ in different persons with CML. BCL11A encodes a transcription factor and is aberrantly-expressed in several haematological and solid neoplasms. We analyzed BCL11A mRNA levels in subjects with chronic and acute phase CML. BCL11A transcript levels were increased in subjects with CML in acute phase compared with those in normals and in subjects in chronic phase including some subjects studied in both phases. BCL11A mRNA levels were correlated with percent bone marrow blasts and significantly higher in lymphoid versus myeloid blast crisis. Differentiation of K562 with butyric acid, a CML cell line, decreased BCL11A mRNA levels. Cytology and flow cytometry analyses showed that ectopic expression of BCL11A in K562 cells blocked differentiation. These data suggest BCL11A may operate in transformation of CML from chronic to acute phase in some persons.

BCL11A expression in acute myeloid leukemia.

BACKGROUND: BCL11A encodes a C2H2 type zinc-finger protein. During normal haematopoietic cell differentiation BCL11A expression is down-regulated. Data in mice suggest up-regulation of BCL11A is involved in the pathogenesis of myeloid leukaemias. BCL11A expression in persons with acute myeloid leukaemia (AML) is not systematically studied. OBJECTIVE: Interrogate associations between BCL11A expression at diagnosis and clinical and laboratory valuables and outcomes in newly-diagnosed persons with AML. METHODS: We determined BCL11A mRNA levels in bone marrow and blood mononuclear cells in 292 consecutive newly-diagnosed subjects with AML by reverse transcript and real-time polymerase chain reaction. Data were compared to mRNA levels in bone marrow cells of normals. RESULTS: Subjects with BCL11A transcript levels at diagnosis exceeding the median value of 2.434 (±3.423 SD; 25th-75th inter-quartile range, 1.33-4.29) had higher WBC levels, a greater proportion of bone marrow myeloblasts, were more likely to be FAB M0 subtype, less likely to be FAB M3 subtype, more likely to be in the intermediate cytogenetic risk cohort, less likely to have a complex karyotype and more likely to have DNMT3A(R882) and FLT3-ITD mutations than subjects with transcript levels below the median value. In 89 subjects receiving conventional induction chemotherapy the complete remission rate was 54% (95% confidence interval [CI]; 33, 75%) in the lower BCL11A cohort and 65% (45, 85%; P=0.26) in the higher BCL11A cohort. 3 year survival was 33% (2, 65%) in the lower BCL11A cohort and 15% (0, 39%; P=0.35) in the high BCL11A cohort. CONCLUSION: BCL11A transcript levels at diagnosis was significantly associated with several clinical and laboratory variables. There were also non-significant associations with complete remission rate and survival. These data suggest a possible role for BCL11A expression in AML biology.