A comparative study of machine learning algorithms for predicting domestic violence vulnerability in Liberian women.

Domestic violence against women is a prevalent in Liberia, with nearly half of women reporting physical violence. However, research on the biosocial factors contributing to this issue remains limited. This study aims to predict women's vulnerability to domestic violence using a machine learning approach, leveraging data from the Liberian Demographic and Health Survey (LDHS) conducted in 2019-2020. We employed seven machine learning algorithms to achieve this goal, including ANN, KNN, RF, DT, XGBoost, LightGBM, and CatBoost. Our analysis revealed that the LightGBM and RF models achieved the highest accuracy in predicting women's vulnerability to domestic violence in Liberia, with 81% and 82% accuracy rates, respectively. One of the key features identified across multiple algorithms was the number of people who had experienced emotional violence. These findings offer important insights into the underlying characteristics and risk factors associated with domestic violence against women in Liberia. By utilizing machine learning techniques, we can better predict and understand this complex issue, ultimately contributing to the development of more effective prevention and intervention strategies.

Human cytomegalovirus immediate early proteins promote degradation of connexin 43 and disrupt gap junction communication: implications for a role in gliomagenesis.

A lack of gap junctional intercellular communication (GJIC) is common in cancer. Many oncogenic viruses have been shown to downregulate the junctional protein connexin 43 (Cx43) and reduce GJIC. Human cytomegalovirus (HCMV) is a ubiquitous, species-specific betaherpesvirus that establishes life-long latency after primary infection. It encodes two viral gene products, immediate early (IE) proteins IE1 and IE2, which are crucial in viral replication and pathogenesis of many diseases. Emerging evidence demonstrates that HCMV DNA and proteins are highly prevalent in glioblastoma multiforme (GBM) and in other tumors, but HCMV's role in tumorigenesis remains obscure. In the present study, we examined the effects of HCMV infection on Cx43 expression and GJIC as well as the viral mechanism mediating the effects in human GBM cells and tissue samples. We found that HCMV downregulated Cx43 protein, resulting in disruption of functional GJIC as assayed by fluorescent dye transfer assay. We show that both HCMV-IE72 and IE86 mediate downregulation of Cx43 by silencing RNA targeting either IE72 or IE86 coupled with ganciclovir. This finding was further validated by transfection with expression vectors encoding IE72 or IE86, and we show that viral-mediated Cx43 depletion involved proteasomal degradation. Importantly, we also observed that the Cx43 protein levels and IE staining correlated inversely in 10 human GBM tissue specimens. Thus, HCMV regulates Cx43 expression and GJIC, which may contribute to gliomagenesis.

Human cytomegalovirus induces upregulation of arginase II: possible implications for vasculopathies.

Both human cytomegalovirus (HCMV) and arginase II (ARG II) have been implicated in the pathogenesis of cardiovascular diseases. The effects of HCMV on ARG II are unknown. The aim of this study was to investigate the effects of HCMV on ARG II expression in endothelial and vascular smooth muscle cells (SMC) both in vitro and ex vivo. Endothelial and SMC were infected with either HCMV or UV-irradiated HCMV. Expression of ARG II, endothelial or inducible nitric oxide synthase (eNOS and iNOS, respectively) and viral immediate early (IE) was quantified using quantitative PCR. Ganciclovir and short interfering RNA were used to determine the viral gene mediating the effects on ARG II. Detection of viral antigens and ARG II expression was performed by immunofluorescence or immunohistochemistry. HCMV infection increased both ARG II mRNA and protein levels in the examined cells; this effect was mediated by the HCMV IE2-p86 protein. The upregulation of ARG II was accompanied by a downregulation of eNOS but an induction of iNOS in HCMV-infected endothelial cells. Both eNOS and iNOS expressions were induced in HCMV-infected SMC. ARG II was abundantly expressed in endothelial cells, foam cells and SMC and was importantly significantly upregulated in HCMV-immunoreactive human carotid atherosclerotic plaques. HCMV IE2-p86 mediates ARG II upregulation in vitro and ARG II is co-expressed with HCMV antigens in human carotid atherosclerotic plaques. We speculate that HCMV may contribute to endothelial dysfunction via ARG II induction and reduced eNOS production.

Prevalence and determinants of hypertension in South-Asian Urban Communities: findings from Demographic and Health Surveys (DHS) data of South Asian countries.

Hypertension increases risk of stroke and other cardiovascular diseases, however, its prevalence and determinants in South Asian urban communities using country representative community-based datasets is lacking. This study evaluated prevalence of hypertension and it's determinants among urban residents of three South Asian countries. Urban population data from demographic and health surveys in Bangladesh, India, and Nepal were extracted. Hypertension prevalence was defined as systolic/diastolic blood pressure ≥ 140/ 90 mmHg. Age, education, wealth, physical activity, alcohol, BMI were considered as risk factors associated with the increased risk of hypertension. We performed binary logistic regression and calculated adjusted Odds Ratios (AOR) with 95% confidence interval (CI) to assess factors related to hypertension. Hypertension prevalence was 37.4% in India, 25.1% in Bangladesh and 18.4% in Nepal. Prevalence increased with age in all settings. Females had reduced odds of hypertension in Bangladesh (AOR 0.75; CI: 0.69, 0.81) and Nepal (AOR 0.62; CI: 0.54, 0.71), but higher risk in India (AOR 2.54; CI: 2.45, 2.63). Low education, caffeine consumption, obesity was associated with higher prevalence of hypertension in all three countries. Smokers had increased odds of hypertension in India (AOR 1.11; CI: 1.06, 1.15) and Nepal (AOR 1.23; 1.02, 1.47). Overall, hypertension prevalence is high in all three countries. Modifiable socioeconomic and lifestyle factors (education, wealth index, smoking status, caffeine consumption and BMI) associated with hypertension. Comprehensive hypertension pacific and sensitive interventions (including behavioral modification treatments and timely screening and access to health care) are urgently needed to prevent and control hypertension among urban populations in South Asia.

Implementation of jute-based nose holder in surgical masks to reduce plastic contamination.

Plastic, in all its forms, always harms the environment, humans, and other living organisms. The coronavirus situation exacerbates the use of plastic products more than at any other time, of which surgical masks contribute to plastic pollution the most. These masks spread to terrestrial and aquatic environments, where they break down into even more noxious microplastics. These microplastics enter the human food chain through water and fish, causing severe damage to the lungs, kidneys, and intestines and even causing death. In this paper, a jute nose holder mask was prepared as an alternative to typical masks to reduce plastic pollution. The jute nose holder was produced with a modified jute flyer-spinning frame machine, where jute was used as the sheath and metal wire was applied as the core component. The nose holder was later coated with starch-based natural gum. Then, the non-woven fabric of 75 grams per square meter (GSM), and the jute nose holder were used to produce the alternative, environmentally friendly mask, which might reduce the 773 tons of plastic waste generated daily from the nose holder of the mask. This alternative mask was then distributed to 900 people for a survey to find out their opinion. From the results of the survey, it is seen that 82.6% of people felt no problem in the nose when they put on the given mask. 85.6% considered the mask more comfortable than the traditional mask, and it was rated above average by 79.8% of the surveyors. So, this study suggests that the given mask can be a sustainable alternative to traditional masks.

Trends and patterns of inequalities in using facility delivery among reproductive-age women in Bangladesh: a decomposition analysis of 2007-2017 Demographic and Health Survey data.

OBJECTIVES: The prime objectives of the study were to measure the prevalence of facility delivery, assess socioeconomic inequalities and determine potential associated factors in the use of facility delivery in Bangladesh.DesignCross-sectional. SETTING: The study involved investigation of nationally representative secondary data from the Bangladesh Demographic and Health Survey between 2007 and 2017-2018. PARTICIPANTS: The participants of this study were 30 940 (weighted) Bangladeshi women between the ages of 15 and 49. METHODS: Decomposition analysis and multivariable logistic regression were both used to analyse data to achieve the study objectives. RESULTS: The prevalence of using facility delivery in Bangladesh has increased from 14.48% in 2007 to 49.26% in 2017-2018. The concentration index for facility delivery utilisation was 0.308 with respect to household wealth status (p<0.001), indicating that use of facility delivery was more concentrated among the rich group of people. Decomposition analysis also indicated that wealth quintiles (18.31%), mothers' education (8.78%), place of residence (7.75%), birth order (5.56%), partners' education (4.30%) and antenatal care (ANC) seeking (8.51%) were the major contributors to the prorich socioeconomic inequalities in the use of facility delivery. This study found that women from urban areas, were overweight, had any level of education, from wealthier families, had ANC, and whose partners had any level of education and involved in business were more likely to have facility births compared with their respective counterparts. CONCLUSIONS: This study found a prorich inequality in the use of facility delivery in Bangladesh. The socioeconomic disparities in facility delivery must be addressed if facility delivery usage is to increase in Bangladesh.

Factors associated with age of mother at first birth in Albania: application of quantile regression model.

The objective of this study was to explore the risk factors that can determine the age of mother at first birth in Albania. The necessary information was extracted from a nationally representative sample survey, Albania Demographic and Health Survey, 2017-18 dataset. To identify the possible risk factors of the age of mother at first birth, we applied quantile regression model. The mean age of mother at first birth was found to be 22.38 years with standard deviation of 3.56 years. The minimum and maximum age was reported 15 and 45 years, respectively. From the result of quantile regression, respondent's current age, education level and partner's higher education level were found positive impact on age of the mother at first birth. However, rural area, partner's age and smoking status found negative impact on age of the mother at first birth. This study suggests that women's education should be more prioritized because it can interfere with the idea of early marriage. Awareness can also be raised by social activities since the improvement of social conditions and reduction of social deprivation can increase the age of mother at first birth.

Costus pictus D. Don leaf extract stimulates GLP-1 secretion from GLUTag L-cells and has cytoprotective effects in BRIN-BD11 ß-cells.

ETHNOPHARMACOLOGICAL RELEVANCE: Costus pictus D. Don, commonly known as insulin plant, is a traditional Indian antidiabetic herbal medicine with glucose-lowering and insulin secretory effects having been reported in animal models and humans with Type 2 diabetes. However, its effects on GLP-1 secretion from intestinal endocrine L-cells and potential metabolic and protective effects in insulin secreting pancreatic ß-cells are not yet fully understood. AIM OF THE STUDY: This study is aimed to elucidate the effects of Costus pictus D. Don leaf extract (CPE) on L-cell function and GLP-1 secretion using the established murine GLUTag L-cell model and to investigate its potential cytoprotective effects against detrimental effects of palmitate and cytokines in pancreatic ß-cells using BRIN-BD11 cells. METHODS: Costus pictus D. Don dried leaf powder was extracted by soxhlet method. Cell viability was determined by MTT assay. Changes in gene and protein expression were quantified by qPCR and western blotting, respectively. GLP-1 and insulin secretion were measured by ELISA. RESULTS: CPE significantly enhanced the percentage of viable BRIN-BD11 and GLUTag cells and protected BRIN-BD11 cells against palmitate- and proinflammatory cytokine-induced toxicity. CPE enhanced acute GLP-1 secretion 6.4-16.3-fold from GLUTag cells at both low (1.1 mM) and high (16.7 mM) glucose (P < 0.01) concentrations. Antioxidant (Nrf2, Cat & Gpx1) and pro-proliferative (Erk1 and Jnk1) gene expression were upregulated by 24 h culture with CPE, while proinflammatory transcription factor NF-κB was downregulated. CONCLUSION: Diminished postprandial GLP-1 secretion and loss of insulin secreting ß-cells are known contributors of T2DM. Our data suggests that CPE acutely stimulates GLP-1 secretion from L-cells. Long term exposure of the BRIN-BD11 cells to CPE enhances cell number and may protect against palmitate and proinflammatory cytokines by activating multiple pathways. Thus, the current study suggests that the possible antidiabetic properties of CPE may be linked to enhanced GLP-1 secretion and ß-cell protection which could be beneficial in the management of T2DM.

Element distribution is altered in a zone surrounding human glioblastoma multiforme.

Recent data indicate that A(1) adenosine receptor (A(1)AR) density is increased in a zone surrounding human and experimental gliomas. On the contrary, tumor tissue and adjacent brain tissue show low to intermediate A(1)AR densities. In order to assess whether changes in A(1)AR expression are indicating further processes of a chemical reorganization of the peritumoral zone, we investigated element concentrations and distribution patterns of copper and zinc in six human glioblastoma multiforme (GBM) specimens by laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS). Uranium and lead were used as external standards. Copper and zinc levels were increased in a peritumoral zone corresponding to the region of elevated A(1)AR density. They showed a lower density in the solid tumor in comparison to surrounding brain tissue, although the cellular density was higher within GBM. Our findings suggest that the immediate vicinity of GBM is characterized by increased levels of copper and zinc supporting the view that higher A(1)AR density surrounding GBM is not an isolated alteration of peritumoral tissue but an indicator of complex changes in the vicinity of infiltrative tumors. Further research is needed to explore the pathophysiological consequences of altered peritumoral element distribution.

Human Cytomegalovirus Up-Regulates Endothelin Receptor Type B: Implication for Vasculopathies?

Background. Both endothelin receptor type B ([ETBR], a G protein-coupled receptor that mediates the vascular effects of the potent vasoconstrictor endothelin-1) and human cytomegalovirus ([HCMV], a ubiquitous herpesvirus) have been implicated in the pathogenesis of cardiovascular disease (CVD). The effects of HCMV infection on ETBR expression are unknown. We hypothesized that HCMV may contribute to the pathogenesis of CVD via ETBR modulation. Methods. Human CMV effects on ETBR were studied in vitro in endothelial cells (ECs) and smooth muscle cells (SMCs) and ex vivo in human carotid plaque tissue specimens. Expression of ETBR and viral immediate-early were quantified using quantitative polymerase chain reaction. Functional consequences after ETBR blockade in ECs were examined by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide proliferation, wound healing, tube formation, and flow adhesion assays. Results. Human CMV is capable of upregulating both ETBR mRNA and protein expression in ECs and SMCs. The ETBR was also abundantly expressed in ECs, foam cells, and SMCs, and, more importantly, in HCMV-positive cells in human carotid plaques. Endothelin receptor type B blockade led to decreased proliferation and reduced tumor necrosis factor α-mediated leukocyte recruitment in both uninfected and HCMV-infected ECs. Direct HCMV infection was antimigratory and antiangiogenic in ECs. Conclusions. Human CMV may contribute to CVD via ETBR induction.

Human cytomegalovirus particles directly suppress CD4 T-lymphocyte activation and proliferation.

CD4 T cells are important regulators of the immune system and are vital for mounting a strong immune response against viral infections. Human cytomegalovirus (HCMV) is known to be a strong modulator of the innate as well as adaptive immune responses. In this study, we found that HCMV directly inhibited proliferation of CD4 T cells and rendered them unresponsive to immunological stimuli. This effect was not observed when CD4 T cells were treated with herpes simplex virus-1/2 or measles virus. When stimulated with phytohemagglutinin, concanavalin A, or phorbol myristate acetate, HCMV-treated T cells were unable to proliferate, revealing an ability of HCMV to inhibit CD4 T cell response. Furthermore, HCMV also prevented proliferation of leukemic T-cell lines. HCMV-treated CD4 T cells expressed the activation markers CD45RO and CD69, were not apoptotic and produced decreased levels of the cytokines IL-4, IFN-γ and TNF-α, compared to untreated controls. The inhibitory effect of HCMV on CD4 T cell proliferation was not mediated by HCMV gH, gB or other immunogenic glycoproteins, since intravenous immunoglobulins or gB- or gH-specific neutralizing antibodies did not prevent the suppression of T-cell proliferation. Our observations show that HCMV inhibits CD4 T cell function with potential clinical consequences for both humoral and cell-mediated immune responses.

HDAC inhibitor 4-phenylbutyrate preserves immature phenotype of human embryonic midbrain stem cells: implications for the involvement of DNA methyltransferase.

Cell replacement and gene therapy using neural stem cells (NSCs) have been widely touted as a promising treatment for CNS diseases including brain tumors. Histone deacetylase (HDAC) inhibitors have been used to explore mechanisms behind the lineage-specific differentiation of NSCs and as modulators of gene therapy. We have used the human embryonic midbrain stem cell line NGC-407 and the HDAC inhibitor 4-phenylbutyrate (4-PB) to investigate the differentiation from epigenetic perspectives. NGC-407 cells can differentiate into both neurons and glial cells, evidenced by morphological characteristics as well as up-regulation of the respective markers ß-tubulin III and glial fibrillary acidic protein (GFAP) and simultaneous down-regulation of the NSC-marker nestin. Genomic DNA extracted from the differentiating cells was globally more methylated than that of the proliferating cells. The differentiating cells showed increased expression of the de novo DNA methyltransferase DNMT3B along with strong immunoreactivity in the cell nuclei. When these cells were treated with 4-PB, both the astrocytic and the neuronal differentiation phenotypes were suppressed, which paralleled a substantially weakened DNMT3B immunoreactivity in the cell nuclei. Importantly, 4-PB treatment preserves the immature phenotype of these differentiating cells as indicated by Western blot analysis and immunocytochemical analyses of the NSC markers, nestin and CD133. Nestin becomes entirely degraded 5 days after induction of differentiation, but upon exposure to 4-PB, some of the differentiating cells retain the integrity of nestin and concurrently, CD133 is also up-regulated. Taken together, the data suggests that HDAC activity is necessary for human embryonic NSC differentiation.

Genomic DNA hypomethylation by histone deacetylase inhibition implicates DNMT1 nuclear dynamics.

Histone deacetylase inhibitors (HDACi) are promising antitumor drugs acting through reactivation of silenced tumor suppressor genes. Several HDACi are currently in clinical trials both for hematological and solid tissue malignancies. Cooperative action of HDACi and DNA methylation inhibitors (DNMTi) has been reported, making combined treatment an attractive choice for cancer therapy. There is some evidence that synergistic effects of HDACi and DNMTi are achieved by their action on common targets, including DNA methyltransferase 1 (DNMT1). To further analyze this interaction, we investigated the effect of the HDACi trichostatin A on global and gene-specific DNA methylation and applied methods with single molecule sensitivity, confocal laser scanning microscopy with avalanche photodiode detectors (APD imaging) and fluorescence correlation spectroscopy (FCS), to study its effect on the nuclear dynamics of DNMT1 in live cells. Our data show that trichostatin A treatment reduces global DNA methylation and the DNMT1 protein level and alters DNMT1 nuclear dynamics and interactions with chromatin. The mechanisms underlying these effects are apparently distinct from the mechanisms of action of the DNMT inhibitor 5-azacytidine. Our study sheds light on the molecular mechanisms underlying the synergistic action of HDACi and DNMTi and may also help to define improved policies for cancer treatment.

Detection of human cytomegalovirus in medulloblastomas reveals a potential therapeutic target.

Medulloblastomas are the most common malignant brain tumors in children. They express high levels of COX-2 and produce PGE2, which stimulates tumor cell proliferation. Human cytomegalovirus (HCMV) is prevalent in the human population and encodes proteins that provide immune evasion strategies and promote oncogenic transformation and oncomodulation. In particular, HCMV induces COX-2 expression; STAT3 phosphorylation; production of PGE2, vascular endothelial growth factor, and IL-6; and tumor formation in vivo. Here, we show that a large proportion of primary medulloblastomas and medulloblastoma cell lines are infected with HCMV and that COX-2 expression, along with PGE2 levels, in tumors is directly modulated by the virus. Our analysis indicated that both HCMV immediate-early proteins and late proteins are expressed in the majority of primary medulloblastomas. Remarkably, all of the human medulloblastoma cell lines that we analyzed contained HCMV DNA and RNA and expressed HCMV proteins at various levels in vitro. When engrafted into immunocompromised mice, human medulloblastoma cells induced expression of HCMV proteins. HCMV and COX-2 expression correlated in primary tumors, cell lines, and medulloblastoma xenografts. The antiviral drug valganciclovir and the specific COX-2 inhibitor celecoxib prevented HCMV replication in vitro and inhibited PGE2 production and reduced medulloblastoma tumor cell growth both in vitro and in vivo. Ganciclovir did not affect the growth of HCMV-negative tumor cell lines. These findings imply an important role for HCMV in medulloblastoma and suggest HCMV as a novel therapeutic target for this tumor.

Targeting the insulin-like growth factor-1 receptor by picropodophyllin as a treatment option for glioblastoma.

Glioblastoma (GB) is the most common malignant brain tumor in adults. It has limited treatment opportunities and is almost exclusively fatal. Owing to the central role the insulin-like growth factor-1 receptor (IGF-1R) plays in malignant cells, it has been suggested as a target for anticancer therapy including GB. The cyclolignan picropodophyllin (PPP) inhibits IGF-1R without affecting the highly homologous insulin receptor. Here, we show that PPP inhibits growth of human GB cell lines along with reduced phosphorylation of IGF-1R and AKT. In vivo, PPP-treatment causes dramatic tumor regression not only in subcutaneous xenografts but also in intracerebral xenografts, indicating passage of PPP across the blood-brain barrier.

Plant thymidine kinase 1: a novel efficient suicide gene for malignant glioma therapy.

The prognosis for malignant gliomas remains poor, and new treatments are urgently needed. Targeted suicide gene therapy exploits the enzymatic conversion of a prodrug, such as a nucleoside analog, into a cytotoxic compound. Although this therapeutic strategy has been considered a promising regimen for central nervous system (CNS) tumors, several obstacles have been encountered such as inefficient gene transfer to the tumor cells, limited prodrug penetration into the CNS, and inefficient enzymatic activity of the suicide gene. We report here the cloning and successful application of a novel thymidine kinase 1 (TK1) from the tomato plant, with favorable characteristics in vitro and in vivo. This enzyme (toTK1) is highly specific for the nucleoside analog prodrug zidovudine (azidothymidine, AZT), which is known to penetrate the blood-brain barrier. An important feature of toTK1 is that it efficiently phosphorylates its substrate AZT not only to AZT monophosphate, but also to AZT diphosphate, with excellent kinetics. The efficiency of the toTK1/AZT system was confirmed when toTK1-transduced human glioblastoma (GBM) cells displayed a 500-fold increased sensitivity to AZT compared with wild-type cells. In addition, when neural progenitor cells were used as delivery vectors for toTK1 in intracranial GBM xenografts in nude rats, substantial attenuation of tumor growth was achieved in animals exposed to AZT, and survival of the animals was significantly improved compared with controls. The novel toTK1/AZT suicide gene therapy system in combination with stem cell-mediated gene delivery promises new treatment of malignant gliomas.

HDAC inhibition amplifies gap junction communication in neural progenitors: potential for cell-mediated enzyme prodrug therapy.

Enzyme prodrug therapy using neural progenitor cells (NPCs) as delivery vehicles has been applied in animal models of gliomas and relies on gap junction communication (GJC) between delivery and target cells. This study investigated the effects of histone deacetylase (HDAC) inhibitors on GJC for the purpose of facilitating transfer of therapeutic molecules from recombinant NPCs. We studied a novel immortalized midbrain cell line, NGC-407 of embryonic human origin having neural precursor characteristics, as a potential delivery vehicle. The expression of gap junction protein connexin 43 (Cx43) was analyzed by western blot and immunocytochemistry. While Cx43 levels were decreased in untreated differentiating NGC-407 cells, the HDAC inhibitor 4-phenylbutyrate (4-PB) increased Cx43 expression along with increased membranous deposition in both proliferating and differentiating cells. Simultaneously, Ser 279/282-phosphorylated form of Cx43 was declined in both culture conditions by 4-PB. The 4-PB effect in NGC-407 cells was verified by using HNSC.100 human neural progenitors and Trichostatin A. Improved functional GJC is of imperative importance for therapeutic strategies involving intercellular transport of low molecular-weight compounds. We show here an enhancement by 4-PB, of the functional GJC among NGC-407 cells, as well as between NGC-407 and human glioma cells, as indicated by increased fluorescent dye transfer.

HDACi phenylbutyrate increases bystander killing of HSV-tk transfected glioma cells.

Malignant glioma patients have a dismal prognosis with an urgent need of new treatment modalities. Previously developed gene therapies for brain tumors showed promising results in experimental animal models, but failed in clinical trials due to low transfection rates and insufficient expression of the transgene in tumor cells, as well as low bystander killing effects. We have previously shown that the histone deacetylase inhibitor 4-phenylbutyrate (4-PB) enhances gap junction communication between glioma cells in culture. In this study, we demonstrate an activation of recombinant HSV-tk gene expression, and a dramatic enhancement of gap junction-mediated bystander killing effect by administration of the HSV-tk prodrug ganciclovir together with 4-PB. These findings that 4-PB potentiates "suicide gene" expression as well as enhances gap junctional communication and bystander killing of tumor cells justify further testing of this paradigm as an adjunct to suicide gene therapy of malignant gliomas.