Auto-hematopoietic stem cell transplantation or chemotherapy? Meta-analysis of clinical choice for AML.

For patients with acute myeloid leukemia (AML) who are not candidates for allogeneic stem cell transplantation (SCT) or do not have a human leukocyte antigen (HLA)-matched donor, it is unclear whether autologous SCT (ASCT) has a better prognosis after the first complete response (CR1) compared to further chemotherapy treatment. A meta-analysis evaluating ASCT compared to further chemotherapy for AML patients in CR1 was performed. The Medline, Embase, Cochrane Controlled Trials Registry, Cochrane Library, Web of Science, and National Knowledge Infrastructure of China databases were searched for relevant literature as of May 26, 2023. Eligible studies included prospectively enrolled adults with AML and randomized first-time respondent patients who did not have a matched sibling donor. Fourteen randomized controlled trials were identified and included 4281 participants, of which 1499 patients received ASCT and 2782 underwent chemotherapy and continued follow-up. In patients with AML in CR1, a lower relapse rate was associated with ASCT compared to chemotherapy [odds ratio (OR) = 0.49, 95% confidence interval (CI) = 0.41-0.57]. Significant disease-free survival (DFS; OR = 1.37, 95% CI = 1.02-1.84) and relapse-free survival (RFS; OR = 2.78, 95% CI = 1.28-6.02) ASCT benefits were documented, and there was no difference in the overall survival (OS) when the studies were pooled (OR = 1.12, 95% CI = 0.85-1.48). The study results indicated that after the first remission, AML patients receiving autologous stem cell transplantation had higher DFS and RFS, similar OS, and lower relapse compared to patients undergoing chemotherapy treatment. This indicated that autologous stem cell transplantation may have a better prognosis.

Compliant Clients: Catechols Exhibit Enhanced Solubility and Stability in Diverse Complex Coacervates.

Polyelectrolyte coacervates, with their greater-than-water density, low interfacial energy, shear thinning viscosity, and ability to undergo structural arrest, mediate the formation of diverse load-bearing macromolecular materials in living organisms as well as in industrial material fabrication. Coacervates, however, have other useful attributes that are challenging to study given the metastability of coacervate colloidal droplets and a lack of suitable analytical methods. We adopt solution electrochemistry and nuclear magnetic resonance measurements to obtain remarkable insights about coacervates as solvent media for low-molecular-weight catechols. When catechols are added to dispersions of coacervated polyelectrolytes, there are two significant consequences: (1) catechols preferentially partition up to 260-fold into the coacervate phase, and (2) coacervates stabilize catechol redox potentials by up to +200 mV relative to the equilibrium solution. The results suggest that the relationship between phase-separated polyelectrolytes and their client molecules is distinct from that existing in aqueous solution and has the potential for insulating many redox-unstable chemicals.

Spectral decoupling of cooperative emissivity in silica-polymer metamaterials for radiative cooling.

Silica-polymer metamaterials are one promising candidate of radiative-cooling materials suitable for scalable manufacture. However, the strong coupling between the silica and polymer components and their respective contribution to total emission remain unexplored. In this work, we developed a 3D full-wave model for such a randomized composite system to retrieve the spectral emissivity of individual components and uncover the interacted physical mechanisms. The results demonstrate and decouple the cooperative emission in the scatter-medium system and quantitatively evaluate the geometry-dependent light-matter interactions, which sheds more light on silica-polymer metamaterials and provides helpful guidance for designing similar thermal-control materials.

Coassembly of a New Insect Cuticular Protein and Chitosan via Liquid-Liquid Phase Separation.

Insect cuticle is a fiber-reinforced composite material that consists of polysaccharide chitin fibers and a protein matrix. The molecular interactions between insect cuticle proteins and chitin that govern the assembly and evolution of cuticles are still not well understood. Herein, we report that Ostrinia furnacalis cuticular protein hypothetical-1 (OfCPH-1), a newly discovered and most abundant cuticular protein from Asian corn borer O. furnacalis, can form coacervates in the presence of chitosan. The OfCPH-1-chitosan coacervate microdroplets are initially liquid-like but become gel-like with increasing time or salt concentration. The liquid-to-gel transition is driven by hydrogen-bonding interactions, during which an induced ß-sheet structure of OfCPH-1 is observed. Given the abundance of OfCPH-1 in the cuticle of O. furnacalis, this liquid-liquid phase separation process and its aging behavior could play critical roles in the formation of the cuticle.

Effective production of S-allyl-L-cysteine through a homogeneous reaction with activated endogenous γ-glutamyltranspeptidase in garlic (Allium Sativum).

S-allyl-L-cysteine (SAC) is a bioactive compound in garlic (Allium sativum). A novel process including soaking and homogeneous reaction was applied for the effective production of SAC with endogenous γ-glutamyltranspeptidase (γ-GTP, EC 2.3.2.2) in garlic. The effects of temperature and CaCl2 concentration on γ-GTP activity in soaking, and the relationship of SAC production with γ-GTP activity in homogeneous reaction were investigated, using fresh garlic as raw material. The experimental results showed that the γ-GTP in fresh garlic was activated by soaking. The yield rate and the final content of SAC increased linearly with increasing initial γ-GTP activity in the homogeneous reaction at 37 °C. The final SAC content reached 606.3 µg/g (i.e. 32 times higher than that in fresh garlic) after soaking for 72 h in a 10-mM CaCl2 solution at 10 °C, and the homogeneous reaction for 8 h at 37 °C. SAC was produced effectively through the homogeneous reaction with activated endogenous γ-GTP in garlic.

Vitamin D receptor mutations in patients with hereditary 1,25-dihydroxyvitamin D-resistant rickets.

CONTEXT: Hereditary vitamin D resistant rickets (HVDRR), also known as vitamin D-dependent rickets type II, is an autosomal recessive disorder characterized by the early onset of rickets with hypocalcemia, secondary hyperparathyroidism and hypophosphatemia and is caused by mutations in the vitamin D receptor (VDR) gene. The human gene encoding the VDR is located on chromosome 12 and comprises eight coding exons and seven introns. OBJECTIVES, PATIENTS, AND METHODS: We analyzed the VDR gene of 5 previously unreported patients, two from Singapore and one each from Macedonia (former Yugoslav Republic), Saudi Arabia and Turkey. Each patient had clinical and radiographic features of rickets, hypocalcemia, and the 4 cases that had the measurement showed elevated serum concentrations of 1,25-dihydroxyvitamin D (1,25(OH)(2)D). Mutations were re-created in the WT VDR cDNA and examined for 1,25(OH)(2)D(3)-mediated transactivation in COS-7 monkey kidney cells. RESULTS: Direct sequencing identified four novel mutations and two previously described mutations in the VDR gene. The novel mutations included a missense mutation in exon 3 causing the amino acid change C60W; a missense mutation in exon 4 causing the amino acid change D144N; a missense mutation in exon 7 causing the amino acid change N276Y; and a 2bp deletion in exon 3 5'-splice site (IVS3∆+4-5) leading to a premature stop. CONCLUSIONS: These 4 unique mutations add to the previous 45 mutations identified in the VDR gene in patients with HVDRR.

Interleukin 17A exacerbates atherosclerosis by promoting fatty acid-binding protein 4-mediated ER stress in macrophages.

RATIONALE: Apoptosis and fatty acid-binding protein-4 (FABP4) induced-endoplasmic reticulum (ER) stress in macrophage is an important pathological process in several vascular occlusive diseases, including atherosclerosis, both of which are accelerated by lipids or inflammatory cytokines. OBJECTIVE: To determine whether interleukin 17A (IL-17A) accelerates atherosclerosis through activating FABP4-mediated ER stress in macrophage. METHODS AND RESULTS: We show here that IL-17A induced ER stress in both murine and human-derived macrophages in vitro, and in the atherosclerotic lesions of ApoE-/- mice. Treating ApoE-/- mice with a chemical chaperone alleviated IL-17A-mediated ER stress and macrophage apoptosis, which was accompanied by recovered atherogenesis. Mechanistically, IL-17A up-regulated the expression of FABP4 (aP2), a cytosolic lipid chaperone that is able to promote lipid-induced macrophage ER stress, through NF-κB and ERK/p38 mitogen-activated protein kinase (MAPK) pathways in macrophages. The inhibition of aP2 expression with a specific chemical inhibitor significantly blocked IL-17A-accelerated ER stress and apoptosis in plaque, and partially rescued IL17A-induced atherogenesis. CONCLUSIONS: The data collectively establish a previously unrecognized link between IL-17A and ER stress through cytosolic lipid chaperone aP2 in macrophages and provide a new insight for understanding the role of IL-17A in atherosclerosis.

Bevacizumab-induced immune thrombocytopenia in an ovarian cancer patient with mixed connective tissue disease: case report and literature review.

Drug-induced immune thrombocytopenia is an adverse reaction marked by accelerated destruction of blood platelets. In cancer therapy, thrombocytopenia has many other causes including bone marrow suppression induced by chemotherapeutic agents, infection, and progression of cancer; drug-induced thrombocytopenia can easily be misdiagnosed or overlooked. Here, we present a case of an ovarian cancer patient with a history of mixed connective tissue disease who underwent surgery followed by treatment with paclitaxel, cisplatin, and bevacizumab. The patient developed acute isolated thrombocytopenia after the sixth cycle. Serum antiplatelet antibody testing revealed antibodies against glycoprotein IIb. After we analyzed the whole therapeutic process of this patient, drug-induced immune thrombocytopenia was assumed, and bevacizumab was conjectured as the most probable drug. Thrombocytopenia was ultimately successfully managed using recombinant human thrombopoietin, prednisone, and recombinant human interleukin-11. We provide a summary of existing literature on immune thrombocytopenia induced by bevacizumab and discuss related mechanisms and triggers for drug-induced immune thrombocytopenia. The present case underscores the potential of bevacizumab to induce immune-mediated thrombocytopenia, emphasizing the need for heightened vigilance towards autoimmune diseases or an autoimmune-activated state as plausible triggers for rare drug-induced immune thrombocytopenia in cancer therapy.

Adaptive Adhesions of Barnacle-Inspired Adhesive Peptides.

The strategy of robust adhesion employed by barnacles renders them fascinating biomimetic candidates for developing novel wet adhesives. Particularly, barnacle cement protein 19k (cp19k) has been speculated to be the key adhesive protein establishing the priming layer in the initial barnacle cement construction. In this work, we systematically studied the sequence design rationale of cp19k by designing adhesive peptides inspired by the low-complexity STGA-rich and the charged segments of cp19k. Combining structure analysis and the adhesion performance test, we found that cp19k-inspired adhesive peptides possess excellent disparate adhesion strategies for both hydrophilic mica and hydrophobic self-assembled monolayer surfaces. Specifically, the low-complexity STGA-rich segment offers great structure flexibility for surface adhesion, while the hydrophobic and charged residues can contribute to the adhesion of the peptides on hydrophobic and charged surfaces. The adaptive adhesion strategy identified in this work broadens our understanding of barnacle adhesion mechanisms and offers valuable insights for designing advanced wet adhesives with exceptional performance on various types of surfaces.

Machine learning enabled rational design for dynamic thermal emitters with phase change materials.

Dynamic thermal emitters have attracted considerable attention due to their potential in widespread applications such as radiative cooling, thermal switching, and adaptive camouflage. However, the state-of-art performances of dynamic emitters are still far below expectations. Here, customized to the special and stringent requirement of dynamic emitters, a neural network model is developed to effectively bridge the structural and spectral spaces and further realizes the inverse design with coupling to genetic algorithms, which considers the broadband spectral responses in different phase-states and utilizes comprehensive measures to ensure the modeling accuracy and computational speed. Besides achieving an outstanding emittance tunability of 0.8, the physics and empirical rules have also been mined qualitatively through decision trees and gradient analyses. The study demonstrates the feasibility of using machine learning to obtain the near-perfect performance of dynamic emitters, as well as guiding the design of other thermal and photonic nanostructures with multifunctions.

Report of two unrelated patients with hereditary vitamin D resistant rickets due to the same novel mutation in the vitamin D receptor.

BACKGROUND/AIMS: Two unrelated patients found to have hereditary vitamin D resistant rickets (HVDRR) were admitted to our hospital. METHODS: This article describes the diagnosis, management and molecular basis for their disease. RESULTS: Both patients had severe growth and motor developmental retardation, rickets with chest deformities and pulmonary abnormalities, but no alopecia. Both had hypocalcemia, secondary hyperparathyroidism and susceptibility to pulmonary infections. In both cases, good response with normalization of abnormal biochemistries and healing of rickets was achieved with IV calcium infusion. Subsequently, improvement was maintained with oral calcium. Both children harbored the same unique missense mutation in the vitamin D receptor (VDR) gene that substituted arginine with histidine at amino acid 274 (R274H) in the VDR ligand-binding domain (LBD). R274 is a contact point for the 1alpha-hydroxyl group of 1,25(OH)2D3, the active ligand for the VDR. Functional analyses of the R274H mutation revealed a 100-fold decrease in activity compared to wild-type VDR. CONCLUSION: We describe a novel missense mutation at R274H in the VDR gene that resulted in the HVDRR syndrome in two unrelated children. Vigorous treatment using IV calcium to normalize their hypocalcemia achieved dramatic improvement in these complex and severely ill patients.

Source apportionment and spatial distribution of potentially toxic elements in soils: A new exploration on receptor and geostatistical models.

Potentially toxic element (PTE) pollution is considered as the main soil environmental problem in the world. Source apportionment and spatial pattern of soil PTEs are essential for soil management. US-EPA positive matrix factorization (EPAPMF) and sequential Gaussian simulation (SGS) are general modeling tools for source apportionment and spatial distribution, respectively. Factor analysis with nonnegative constraints (FA-NNC) and stochastic partial derivative equations (SPDE) provided potential tools for this issue. We compared the performance of FA-NNC with PMF and the performance of SPDE with SGS, based on a dataset containing 9 PTEs in 285 topsoil samples. Three factors were determined by the two receptor models, and the source contributions were similar, suggesting that FA-NNC can validly identify quantitative sources of soil PTEs. The average source contributions were calculated based on the PMF and FA-NNC. Natural sources dominated the contents of As, Co, Cr, Cu, Ni, and Zn and affected 56.0%, 38.7%, and 84.8% of the Cd, Hg, and Pb concentrations, respectively. A total of 59.8% of Hg and 12.0% of Pb were associated with atmospheric deposition from coal combustion, industrial and traffic emissions, respectively. Agricultural and industrial activities contributed 37.2% of Cd concentration. SPDE proved to be an effective geostatistical technique to simulate the spatial patterns of soil PTEs with higher prediction accuracy than SGS. Co, Cr, Cu, and Ni had similar spatial patterns with hotspots randomly distributed across the study area. The common hotspots of As, Cd, Hg, Pb, and Zn in central parts inherited their high geochemical background in mudstone, while intensive human inputs in these areas also contributed to the accumulation of Cd, Hg, and Pb.

Hereditary 1,25-dihydroxyvitamin D-resistant rickets with alopecia resulting from a novel missense mutation in the DNA-binding domain of the vitamin D receptor.

The rare genetic recessive disease, hereditary vitamin D resistant rickets (HVDRR), is caused by mutations in the vitamin D receptor (VDR) that result in resistance to the active hormone 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3) or calcitriol). In this study, we examined the VDR from a young boy with clinical features of HVDRR including severe rickets, hypocalcemia, hypophosphatemia and partial alopecia. The pattern of alopecia was very unusual with areas of total baldness, adjacent to normal hair and regions of scant hair. The child failed to improve on oral calcium and vitamin D therapy but his abnormal chemistries and his bone X-rays normalized with intravenous calcium therapy. We found that the child was homozygous for a unique missense mutation in the VDR gene that converted valine to methionine at amino acid 26 (V26M) in the VDR DNA-binding domain (DBD). The mutant VDR was studied in the patient's cultured skin fibroblasts and found to exhibit normal [(3)H]1,25(OH)(2)D(3) binding and protein expression. However, the fibroblasts were unresponsive to treatment with high concentrations of 1,25(OH)(2)D(3) as demonstrated by their failure to induce CYP24A1 gene expression, a marker of 1,25(OH)(2)D(3) responsiveness. We recreated the V26M mutation in the WT VDR and showed that in transfected COS-7 cells the mutation abolished 1,25(OH)(2)D(3)-mediated transactivation. The mutant VDR exhibited normal ligand-induced binding to RXRalpha and to the coactivator DRIP205. However, the V26M mutation inhibited VDR binding to a consensus vitamin D response element (VDRE). In summary, we have identified a novel V26M mutation in the VDR DBD as the molecular defect in a patient with HVDRR and an unusual pattern of alopecia.

Two new unrelated cases of hereditary 1,25-dihydroxyvitamin D-resistant rickets with alopecia resulting from the same novel nonsense mutation in the vitamin D receptor gene.

1,25-Dihydroxyvitamin D3 (1,25(OH)2D3) an important regulator of bone homeostasis, mediates its actions by binding to the vitamin D receptor (VDR), a nuclear transcription factor. Mutations in the VDR cause the rare genetic disease hereditary vitamin D resistant rickets (HVDRR). In this study, we examined two unrelated young female patients who exhibited severe early onset rickets, hypocalcemia, and hypophosphatemia. Both patients had partial alopecia but with different unusual patterns of scant hair. Sequencing of the VDR gene showed that both patients harbored the same unique nonsense mutation that resulted in a premature stop codon (R50X). Skin fibroblasts from patient #1 were devoid of VDR protein and 1,25(OH)2D3 treatment of these cells failed to induce CYP24A1 gene expression, a marker of 1,25(OH)2D3 action. In conclusion, we identified a novel nonsense mutation in the VDR gene in two patients with HVDRR and alopecia. The mutation truncates the VDR protein and causes 1,25(OH)2D3 resistance.

Identifying quantitative sources and spatial distributions of potentially toxic elements in soils by using three receptor models and sequential indicator simulation.

Determining the reliable source contribution and spatial distribution of potentially toxic elements (PTEs) is a focal issue for soil regulation and remediation. For this purpose, three receptor models, US-EPA positive matrix factorization (EPAPMF), weighted alternating least squares positive matrix factorization (WALSPMF), and non-negative constrained absolutely principle analysis (NCAPCA), were used to a dataset consisting of ten PTEs (As, Cd, Co, Cr, Cu, Hg, Mn, Ni, Pb, and Zn) for source apportionment. Hazardous areas of ten PTEs were delineated using sequential indicator simulation (SIS) and uncertainty analysis. Three factors for ten PTEs were derived by three receptor models with a one-to-one correspondence between the factors. To obtain more appropriate results, the three receptor models were combined to calculate the ensemble-average source contributions. As, Co, Cr, Cu, Mn, and Ni were derived from a natural source with ensemble-average contributions higher than 85.72%. Cd, Hg, Pb, and Zn were contributed by both parent material and anthropogenic influence. More than half of Hg concentrations were associated with atmospheric deposition caused by human emissions. The concentrations of 28.04% for Cd, 20.74% for Hg, 43.49% for Pb, and 23.71% for Zn were associated with human inputs including agriculture practice, industrial activities, and vehicle emissions. The maps of spatial distribution generated by the SIS indicated that parent materials controlled the spatial distributions of As, Cd, Co, Cr, Cu, Mn, Ni, Pb, and Zn. 27.1% and 32.1% of the total area for Cd and Hg were identified as hazardous areas exceeding 1.5 times background values of Shandong province.

Empirical Study on the Transparency of Security Risk Information in Chinese Listed Pharmaceutical Enterprises Based on the ANP-DS Method.

Frequent outbreaks of drug safety incidents pose a massive threat to public health and safety, while the transparency of security risk information in medical enterprises is not optimistic. Therefore, this study uses the analytic network process (Dempster-Shafer method) to construct a transparent comprehensive evaluation model for security risk information in listed pharmaceutical enterprises from the perspective of government supervision and listed pharmaceutical enterprises. On the basis of 59,305 data obtained by 303 enterprises listed in the Chinese biomedical sector, this research conducted an empirical study on the transparency of safety risk information in Chinese listed pharmaceutical enterprises. The current study found that the transparency of security risk information in Chinese listed pharmaceutical enterprises is generally between "general" and "relatively good" and tends to be "relatively good." However, administrative punishment information, adverse drug reaction reporting systems, and production processes need continuous improvement.

Predicting future dynamics from short-term time series using an Anticipated Learning Machine.

Predicting time series has significant practical applications over different disciplines. Here, we propose an Anticipated Learning Machine (ALM) to achieve precise future-state predictions based on short-term but high-dimensional data. From non-linear dynamical systems theory, we show that ALM can transform recent correlation/spatial information of high-dimensional variables into future dynamical/temporal information of any target variable, thereby overcoming the small-sample problem and achieving multistep-ahead predictions. Since the training samples generated from high-dimensional data also include information of the unknown future values of the target variable, it is called anticipated learning. Extensive experiments on real-world data demonstrate significantly superior performances of ALM over all of the existing 12 methods. In contrast to traditional statistics-based machine learning, ALM is based on non-linear dynamics, thus opening a new way for dynamics-based machine learning.

The role of insulin-like growth factor binding protein-3 in the growth inhibitory actions of androgens in LNCaP human prostate cancer cells.

Insulin-like growth factor binding protein-3 (IGFBP-3), an antiproliferative and proapoptotic protein, has been shown to be upregulated by growth inhibitory concentrations of androgens in LNCaP human prostate cancer (PCa) cells, but the mechanism of regulation and the role of IGFBP-3 in the modulation of PCa cell proliferation are unknown. In this study, we have examined the effects of a range of concentrations of the synthetic androgen R1881 on IGFBP-3 expression and cell growth in LNCaP cells. We have also investigated the role of androgen-stimulated IGFBP-3 in androgen-induced growth inhibition. We show that low doses of R1881 stimulate LNCaP cell proliferation, but do not induce IGFBP-3 expression, whereas high doses of R1881 that inhibit cell growth, significantly increase expression of IGFBP-3. Importantly, we demonstrate that the combination of calcitriol and androgens not only synergistically upregulates IGFBP-3 expression but also inhibits cell growth better than either hormone alone. siRNA knockdown of IGFBP-3 expression partially reverses the growth inhibition by calcitriol and by androgens. Furthermore, we find that the growth inhibitory dose of R1881 leads to increases in the cyclin dependent kinase inhibitors (CDKIs), p21 and p27 as well as to G1 arrest. These changes can be blocked or partially reversed by IGFBP-3 siRNA, indicating that the induction of CDKIs is downstream of IGFBP-3. Our data suggest, for the first time, that IGFBP-3 is involved in the antiproliferative action of high doses of androgens partly through p21 and p27 pathways and that IGFBP-3 may contribute significantly to androgen-induced changes in LNCaP cell growth.

Concentration estimation of heavy metal in soils from typical sewage irrigation area of Shandong Province, China using reflectance spectroscopy.

Since sewage irrigation can markedly disturb the status of heavy metals in soils, a convenient and accurate technique for heavy metal concentration estimation is of utmost importance in the cropland using wastewater for irrigation. This study therefore assessed the feasibility of visible and near infrared reflectance (VINR) spectroscopy for predicting heavy metal contents including Cr, Cu, Ni, Pb, Zn, As, Cd, and Hg in the north plain of Longkou city, Shandong Province, China. A total of 70 topsoil samples were taken for in situ spectra measurement and chemical analysis. Stepwise multiple linear regression (SMLR) and principal component regression (PCR) algorithms were applied to establish the associations between heavy metals and reflectance spectral data pretreated by different transformation methods. Based on the criteria that minimal root mean square error (RMSE), maximal coefficient of determination (R 2) for calibration, and greater ratio of standard error of performance to standard deviation (RPD) is related to the optimal model, SMLR model using first deviation data (RD1) provided the best prediction for the contents of Ni, Pb, As, Cd, and Hg, calibration using SNV data for Cr and continuum removal spectra for Zn, while PCR equation employed RD1 values was fit for prediction of the contents of Cu. The determination coefficients of all the reasonable models were beyond 0.6, and RPD indicated a fair or good result. In general, first deviation preprocessing tool outperformed other methods in this study, while raw spectra reflectance performed unsatisfactory in all models. Overall, VINR reflectance spectroscopy technique could be applicable to the rapid concentration assessment of heavy metals in soils of the study area.

Growth inhibitory concentrations of androgens up-regulate insulin-like growth factor binding protein-3 expression via an androgen response element in LNCaP human prostate cancer cells.

IGF binding protein-3 (IGFBP-3), the most abundant circulating IGF binding protein, inhibits cell growth and induces apoptosis by both IGF-I-dependent and -independent pathways. The ability of IGFBP-3 to inhibit tumor growth has been demonstrated in many cancers including prostate cancer (PCa). High concentrations of androgens, which inhibit the growth of the LNCaP human PCa cell line, have been shown to have both positive and negative effects on IGFBP-3 expression by different laboratories. To further explore the relationship between IGFBP-3 and androgens, we examined IGFBP-3 expression in LNCaP cells. We demonstrate that IGFBP-3 expression can be induced by 10 nm of the synthetic androgen R1881 or dihydrotestosterone. Transactivation assays show that the 6-kb IGFBP-3 promoter sequence directly responds to androgen treatment. In silico analysis identified a putative androgen response element (ARE) at -2,879/-2,865 in the IGFBP-3 promoter. A single point mutation in this ARE disrupted transactivation by R1881. Combining the data obtained from EMSA, chromatin immunoprecipitation and mutational analysis, we conclude that a novel functional ARE is present in the IGFBP-3 promoter that directly mediates androgen induction of IGFBP-3 expression. Furthermore, we found that the combination of androgens and calcitriol significantly potentiated the IGFBP-3 promoter activity, suggesting that enhanced induction of the expression of the endogenous IGFBP-3 gene may contribute to the greater inhibition of LNCaP cell growth by combined calcitriol and androgens. Because androgens are well known to stimulate PCa growth and androgen deprivation therapy causes PCa to regress, the stimulation by androgens of this antiproliferative and proapoptotic protein is paradoxical and raises interesting questions about the role of androgen-stimulated IGFBP-3 in PCa.