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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Highly Corrosion Resistant and Sandwich-like Si3N4/Cr-CrNx/Si3N4 Coatings Used for Solar Selective Absorbing Applications.

Highly corrosion resistant, layer-by-layer nanostructured Si3N4/Cr-CrNx/Si3N4 coatings were deposited on aluminum substrate by DC/RF magnetron sputtering. Corrosion resistance experiments were performed in 0.5, 1.0, 3.0, and 5.0 wt % NaCl salt spray at 35 °C for 168 h. Properties of the coatings were comprehensively investigated in terms of optical property, surface morphology, microstructure, elemental valence state, element distribution, and potentiodynamic polarization. UV-vis-near-IR spectrophotometer and FTIR measurements show that the change process in optical properties of Si3N4/Cr-CrNx/Si3N4/Al coatings can be divided into three stages: a rapid active degradation stage, a steady passivation stage, and a transpassivation degradation stage. With the increase in the concentration of NaCl salt spray, solar absorptance and thermal emittance experienced a slight degradation. SEM images reveal that there is an increase in surface defects, such as microcracks and holes and -cracks. XRD and TEM measurements indicate that the phase structure changed partially and the content of CrOx and Al2O3 has increased. Auger electron spectroscopy shows that the elements of Cr, N, and O have undergone a minor diffusion. Electrochemical polarization curves show that the as-deposited Si3N4/Cr-CrNx/Si3N4/Al coatings have excellent corrosion resistance of 3633.858 kΩ, while after corroding in 5.0 wt % NaCl salt spray for 168 h the corrosion resistance dropped to 13.759 kΩ. However, these coatings still have an outstanding performance of high solar absorptance of 0.924 and low thermal emittance of 0.090 after corroding in 3.0 wt % NaCl salt spray for 120 h. Thus, the Si3N4/Cr-CrNx/Si3N4/Al coating is a good choice for solar absorber coatings applied in the high-saline environment.

The spread model of food safety risk under the supply-demand disturbance.

In this paper, based on the imbalance of the supply-demand relationship of food, we design a spreading model of food safety risk, which is about from food producers to consumers in the food supply chain. We use theoretical analysis and numerical simulation to describe the supply-demand relationship and government supervision behaviors' influence on the risk spread of food safety and the behaviors of the food producers and the food retailers. We also analyze the influence of the awareness of consumer rights protection and the level of legal protection of consumer rights on the risk spread of food safety. This model contributes to the explicit investigation of the influence relationship among supply-demand factors, the regulation behavioral choice of government, the behavioral choice of food supply chain members and food safety risk spread. And this paper provides a new viewpoint for considering food safety risk spread in the food supply chain, which has a great reference for food safety management.

A multifunctional poly(curcumin) nanomedicine for dual-modal targeted delivery, intracellular responsive release, dual-drug treatment and imaging of multidrug resistant cancer cells.

A multifunctional anti-cancer nanomedicine based on a biotin-poly(ethylene glycol)-poly(curcumin-dithio dipropionic acid) (Biotin-PEG-PCDA) polymeric nanocarrier loaded with paclitaxel (PTX), magnetic nanoparticles (MNPs) and quantum dots (QDs) is developed. It combines advantageous properties of efficient targeted delivery and uptake (via biotin and MNP), intracellular responsive release (via cleavable PCDA polymer), fluorescence imaging (via QD) and combined PTX-curcumin dual-drug treatment, allowing for overcoming drug resistance mechanisms of model multidrug resistant breast cancer cells (MCF-7/ADR). The PTX/MNPs/QDs@Biotin-PEG-PCDA nanoparticles are highly stable under physiological conditions, but are quickly disassembled to release their drug load in the presence of 10 mM glutathione (GSH). The nanoparticles show high uptake by tumour cells from a combined effect of magnet targeting and biotin receptor-mediated internalization. Moreover, curcumin, an intracellularly cleaved product of PCDA, can effectively down regulate the expression of drug efflux transporters such as P-glycoprotein (P-gp) to increase PTX accumulation within target cancer cells, thereby enhancing PTX induced cytotoxicity and therapeutic efficacy against MCF-7/ADR cells. Taken together, this novel tumour-targeting and traceable multifunctional nanomedicine is highly effective against model MDR cancer at the cellular level.

pH and near-infrared light dual-stimuli responsive drug delivery using DNA-conjugated gold nanorods for effective treatment of multidrug resistant cancer cells.

A thiolated pH-responsive DNA conjugated gold nanorod (GNR) was developed as a multifunctional nanocarrier for targeted, pH-and near infrared (NIR) radiation dual-stimuli triggered drug delivery. It was further passivated by a thiolated poly(ethylene glycol)-biotin to improve its cancer targeting ability by specific binding to cancer cell over-expressed biotin receptors. Doxorubicin (DOX), a widely used clinical anticancer drug, was conveniently loaded into nanocarrier by intercalating inside the double-stranded pH-responsive DNAs on the GNR surface to complete the construction of the multifunctional nanomedicine. The nanomedicine can rapidly and effectively release its DOX payload triggered by an acidic pH environment (pH~5) and/or applying an 808nm NIR laser radiation. Compared to free DOX, the biotin-modified nanomedicine displayed greatly increased cell uptake and significantly reduced drug efflux by model multidrug resistant (MDR) breast cancer cell lines (MCF-7/ADR). The application of NIR radiation further increased the DOX release and facilitated its nuclear accumulation. As a result, this new DNA-GNR based multifunctional nanomedicine exerted greatly increased potency (~67 fold) against the MDR cancer cells over free DOX.

[Pollution Assessment and Spatial Distribution Characteristics of Heavy Metals in Soils of Coal Mining Area in Longkou City].

The present paper takes the coal mining area of Longkou City as the research area. Thirty-six topsoil (0-20 cm) samples were collected and the contents of 5 kinds of heavy metals were determined, including Cd, As, Ni, Ph, Cr. Geo-statistics analysis was used to analyze the spatial distribution of heavy metals. Principal component analysis (PCA) was used to explore the pollution sources of heavy metals and the degree of heavy metals pollution was evaluated by weighted average comprehensive pollution evaluation method. The results showed that enrichment phenomenon was significant for the 5 kinds of heavy metals. Taking secondary standard of National Environment Quality Standard for Soil as the background value, their exceed standard rates were 72.22%, 100%, 100%, 91.67%, 100%, respectively. Average contents of heavy metals in the soil samples were all over the national standard level two and were 1.53, 11.86, 2.40, 1.31, 4.09 times of the background value. In addition, the average contents were much higher than the background value of the topsoil in the eastern part of Shandong Province and were 9.85, 39.98, 8.85, 4.29, 12.71 times of the background value. According to the semivariogram model, we obtained the nugget-effects of 5 kinds of heavy metals and their values were in the order of As (0.644) > Cd (0.627) > Cr (0.538) > Ni (0.411) > Pb (0.294), all belonging to moderate spatial correlation. On the whole, the central part of the Sangyuan Coal Mine and its surrounding areas were the most seriously polluted, while the pollution of heavy metals in the east and west of the study area was relatively light. Principal component analysis suggested that the enrichment of Cd, As, Ni, Cr was due to irrigation of wastewater, the discharge of industry and enterprise, and the industrial activity. Automobile exhaust and coal combustion were the main pollution sources of Pb. The single-factor assessment of heavy metals pollution showed that the degree of different heavy metals pollution was in the order of As > Cr > Ni > Cd > Pb. Simultaneously, comprehensive pollution evaluation showed that the degree of heavy metals pollution in the study area was very serious, with comprehensive pollution index ranging from 2.17 to 4.66, among which, the numbers of moderate and heavy pollution samples were 10 and 26, respectively. Areas with heavy pollution were mainly distributed in the Sangyuan Coal Mine, Beizao Coal Mine, Liuhai Coal Mine; and the areas with moderate pollution covered Wali Coal Mine, Liangjia Coal Mine, and other regions. The results of this paper will provide data reference and theoretical support for the study of ecological risk assessment in the study area.

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.

The relationship of freeze tolerance with intracellular compounds in baker's yeasts.

Freeze-tolerant baker's yeasts are required for the processing of frozen doughs. The present study was carried out to investigate the cell survival rate after frozen storage and the change of fermentability in dough due to frozen storage, and to discuss quantitatively the relationship of freeze tolerance with intracellular trehalose, amino acids, and glycerol, using six types of baker's yeasts as the test materials. The experimental results showed that the fermentability of yeast cells in frozen dough was strongly correlated with the cell survival rate. The baker's yeast with a higher level of cell survival rate had a larger increase in the total intracellular compound content after frozen storage, and the cell survival rate increased linearly with increasing total intracellular compound content in frozen yeast cells. Trehalose was a primary compound affecting freeze tolerance, followed by glutamic acid, arginine, proline, asparagic acid, and glycerol. The basic information provided by the present study is useful for exploring the freeze-tolerance mechanisms of baker's yeast cells, breeding better freeze-tolerant baker's yeast strains, and developing more effective cryoprotectants.

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.