Single-Step Low-Temperature Synthesis of Carbon Dots for Advanced Multiparametric Bioimaging Probe Applications.

Carbon dots (CDs) have recently emerged in biomedical and agricultural domains, mainly for their probe applications in developing efficient sensors. However, the existing high-temperature approaches limit the industrial level scaling up to further translate them into different products by mass-scale fabrication of CDs. To address this, we have attempted to lower the synthesis temperature to 140 °C and synthesized different CDs using different organic acids and their combinations in a one-step approach (quantum yield 3.6% to 16.5%; average size 3 to 5 nm). Further, sensing applications of CDs have been explored in three different biological models, mainly Danio rerio (zebrafish) embryos, bacterial strains, and the Lactuca sativa (lettuce) plant. The 72 h exposure of D. rerio embryos to 0.5 and 1 mg/mL concentrations of CDs exhibited significant uptake without mortality, a 100% hatching rate, and nonsignificant alterations in heart rate. Bacterial bioimaging experiments revealed CD compatibility with Gram-positive (Bacillus subtilis) and Gram-negative (Serratia marcescens) strains without bactericidal effects. Furthermore, CDs demonstrated effective conduction and fluorescence within the vascular system of lettuce plants, indicating their potential as in vivo probes for plant tissues. The single-step low-temperature CD synthesis approach with efficient structural and optical properties enables the process as industrially viable to up-scale the technology readiness level. The bioimaging of CDs in different biological models indicates the possibility of developing a CD probe for diverse biosensing roles in diseases, metabolism, microbial contamination sensing, and more.

Structure specific neuro-toxicity of α-synuclein oligomer.

Parkinson's disease (PD) is linked to α-synuclein (aS) aggregation and deposition of amyloid in the substantia nigra region of the brain tissues. In the current investigation we produced two distinct classes of aS oligomer of differed protein conformation, stability and compared their toxic nature to cultured neuronal cells. Lyophilized oligomer (LO) was produced in storage of aS at-20 °C for 7 days and it was enriched with loosely hold molten globule like structure with residues having preferences for α-helical conformational space. The size of the oligomer was 4-5.5 nm under AFM. This kind of oligomer exhibited potential toxicity towards neuronal cell lines and did not transform into compact ß-sheet rich amyloid fiber even after incubation at 37 °C for several days. Formation of another type of oligomer was often observed in the lag phase of aS fibrillation that often occurred at an elevated temperature (37 °C). This kind of heat induced oligomer (IO) was more hydrophobic and relatively less toxic to neuronal cells compared to lyophilized oligomer (LO). Importantly, initiation of hydrophobic zipping of aS caused the transformation of IO into thermodynamically stable ß-sheet rich amyloid fibril. On the other hand, the presence of molten globule like conformation in LO, rendered greater toxicity to cultured neuronal cells.

Synthesis and application of alginate-nanocellulose composite beads for defluoridation process in a batch and fluidized bed reactor.

Electronegative Fluorine has great reactivity and it exists as organic or inorganic fluoride compounds. Biosorption feasibility of fluoride onto alginate-cellulose composites was investigated in this study. Extracted cellulose has been utilized to synthesize calcium alginate impregnated composite beads for fluoride remediation process in batch and fluidized-bed reactors. Physiochemical characteristics were analyzed by FTIR, SEM, TGA and BET. From the BET properties analysis, the surface area of prepared composite beads was 87.13 m2/g. The point zero charge (PZC) value of composite beads was attained at pH 7.32. The relationship between biosorption efficiency and independent variables have been observed to evaluate the effects on the fluoride biosorption efficiency of composites and its components. The hypothetical development of the removal technique has been explained using various nonlinear model-fitting methods to evaluate Isotherm study, bio-sorption Kinetics, Thermodynamic parameters and Mass transfer study. Maximum monolayer adsorption capacity (qm) obtained by following Langmuir model for fluoride removal was found to be 23.809 mg/g at 30 °C using adsorbent dosage of 2 g/L for an initial fluoride concentration of 6 mg/L. The optimized condition for fluoride adsorption experiment was observed by evaluating response surface methodology (RSM) was pH-5.67, dose 1.89 g/L and time 85.71 min and removal was found as 82.79%. Experimental data of fluidized-bed study were evaluated by designing mathematical modeling. Fluidization velocities was adjusted in between Umf and 2Umf for optimizing external mass transfer and adsorbent loss. Regeneration study of fluoride loaded biosorbent and cost analysis of composite production have been estimated.

Single point mutations at the S129 residue of α-synuclein and their effect on structure, aggregation, and neurotoxicity.

Parkinson's disease is an age-related neurological disorder, and the pathology of the disease is linked to different types of aggregates of α-synuclein or alpha-synuclein (aS), which is an intrinsically disordered protein. The C-terminal domain (residues 96-140) of the protein is highly fluctuating and possesses random/disordered coil conformation. Thus, the region plays a significant role in the protein's solubility and stability by an interaction with other parts of the protein. In the current investigation, we examined the structure and aggregation behavior of two artificial single point mutations at a C-terminal residue at position 129 that represent a serine residue in the wild-type human aS (wt aS). Circular Dichroism (CD) and Raman spectroscopy were performed to analyse the secondary structure of the mutated proteins and compare it to the wt aS. Thioflavin T assay and atomic force microscopy imaging helped in understanding the aggregation kinetics and type of aggregates formed. Finally, the cytotoxicity assay gave an idea about the toxicity of the aggregates formed at different stages of incubation due to mutations. Compared to wt aS, the mutants S129A and S129W imparted structural stability and showed enhanced propensity toward the α-helical secondary structure. CD analysis showed proclivity of the mutant proteins toward α-helical conformation. The enhancement of α-helical propensity lengthened the lag phase of fibril formation. The growth rate of ß-sheet-rich fibrillation was also reduced. Cytotoxicity tests on SH-SY5Y neuronal cell lines established that the S129A and S129W mutants and their aggregates were potentially less toxic than wt aS. The average survivability rate was ∼40% for cells treated with oligomers (presumably formed after 24 h of incubation of the freshly prepared monomeric protein solution) produced from wt aS and ∼80% for cells treated with oligomers obtained from mutant proteins. The relative structural stability with α-helical propensity of the mutants could be a plausible reason for their slow rate of oligomerization and fibrillation, and this was also the possible reason for reduced toxicity to neuronal cells.

Pressure Dependence of Solid Electrolyte Ionic Conductivity: A Particle Dynamics Study.

The search for safe, reliable, and compact high-capacity energy storage devices has led to increased interest in all-solid-state battery research. The use of solid electrolytes provides enhanced safety and durability due to their reduced flammability and increased mechanical strength compared to organic liquid electrolytes. Still, the use of solid electrolytes remains challenging. A significant issue is their generally low Li-ion conductivity, which depends on the lattice diffusion of Li ions through the solid phase, as well as on the limited contact area between the electrolyte particles. While the lattice diffusion can be addressed through the chemistry of the solid electrolyte material, the contact area is a mechanical and structural problem of packing and compression of the electrolyte particles depending on their size and shape. This work studies the effect of pressurization on the electrolyte conductivity exploring cases of low as well as high grain boundary (GB) conductivity, compared to the bulk conductivity. Scaling dependence, σ ∼ Pη, of the conductivity σ with pressure P is revealed. For an idealized electrolyte represented as spheres in hexagonal closely packed configuration, η = 2/3 and η = 1/3 have been theoretically calculated for the two cases of low and high GB conductivity, respectively. For randomly packed spheres, the equivalent exponent values were numerically estimated to be approximately 3/4 and 1/2, respectively, which are higher than the closed packed values due to the additional decrease of porosity with the increase in pressure. As demonstrated in the study, experimental measurement of η can indicate which type of bulk or GB conductivity is dominant in a particular electrolyte powder and could be used in addition to electrochemical impedance spectroscopy measurements.

Natural Polymer-Based Thin Film Strategies for Skin Regeneration in Lieu of Regenerative Dentistry.

Wound healing (WH) is a complex and dynamic process that comprises of a series of molecular and cellular events that occur after tissue injury. The injuries of the maxillofacial and oral region caused by trauma or surgery result in undesirable WH such as delayed wound closure and formation of scar tissue. Skin tissue engineering (TE)/regeneration is an emerging approach toward faster, superior, and more effective resolution of clinically significant wounds effectively. A multitude of TE principles approaches are being put to action for the fabrication of hydrogels, electrospun sheets, 3D scaffolds, and thin films that can be used as wound dressings materials, sutures, or skin substitutes. Thin films are advantageous over other materials owing to their flexibility, ability to provide a barrier against external contamination, easy gaseous exchange, and easy monitoring of wounds. This review focuses on wound-dressing films and their significance and discusses various fabrication techniques. In addition, we explore various natural biopolymers that can be used for fabrication of skin TE materials. Impact Statement In this review article, critical evaluations of natural polymers used in skin regeneration were discussed. Further, the fabrication technology of the 2D and 3D material in wound healing were discussed.

Methods to Evaluate the Effects of HAT/KAT Inhibition on SIAH2-Driven Reactive Oxygen Species Generation in Helicobacter pylori-Infected Gastric Epithelial Cells.

Helicobacter pylori infection is one of the leading factors that promotes, among other diseases, gastric cancer (GC). Infection of gastric epithelial cells (GECs) by H. pylori enhances the expression as well as acetylation of the E3 ubiquitin ligase SIAH2 which promotes GC progression. The histone acetyltransferase (HAT) activity of p300 catalyzes SIAH2 acetylation following H. pylori infection. Since reactive oxygen species (ROS) generation in H. pylori-infected GECs accelerates GC progression, acetylation-mediated SIAH2 regulation might be a crucial modifier of ROS generation in the infected GECs. Here, we describe a compendium of methods to evaluate the effects of HAT/lysine acetyl transferase (KAT) inhibitors (HAT/KATi) on SIAH2-mediated ROS regulation in H. pylori-infected GECs.

DNA numerical encoding schemes for exon prediction: a recent history.

Bioinformatics in the present day has been firmly established as a regulator in genomics. In recent times, applications of Signal processing in exon prediction have gained a lot of attention. The exons carry protein information. Proteins are composed of connected constituents known as amino acids that characterize the specific function. Conversion of the nucleotide character string into a numerical sequence is the gateway before analyzing it through signal processing methods. This numeric encoding is the mathematical descriptor of nucleotides and is based on some statistical properties of the structure of nucleic acids. Since the type of encoding extremely affects the exon detection accuracy, this paper is devised for the review of existing encoding (mapping) schemes. The comparative analysis is formulated to emphasize the importance of the genetic code setting of amino acids considered for application related to computational elucidation for exon detection. This work covers much helpful information for future applications.

Enhanced biosorption of fluoride by extracted nanocellulose/polyvinyl alcohol composite in batch and fixed-bed system: ANN analysis and numerical modeling.

The present investigation attempted to examine the defluoridation feasibility onto the extracted nanocellulose/PVA polymer composites. Nanocellulose were derived from sugarcane bagasse and blended with PVA (polyvinyl alcohol) polymer matrix. The defluoridation potential of nanocellulose/PVA was observed to be significantly dependent on the various operational factors including pH, time interval, etc. the Temkin isotherm (R2 = 0.989) as well as the Langmuir isotherm equation (R2 = 0.982) could well fit with the investigational data. Following the Langmuir isotherm, the maximum monolayer adsorption capacity for fluoride elimination at 25°C was obtained as 11.363 mg g-1. The nature of rate-limiting steps involved in defluoridation process might be effectively predicted by pseudo-second-order kinetics. Values of thermodynamic state properties achieved as of the thermodynamic analysis showed that the defluoridation process was spontaneous, exothermic, and feasible. The diffusion and mass transfer study were estimated by following the Boyd's model. Average effective diffusion coefficient (De) at various initial fluoride concentrations (4-10 mg L-1) was obtained as 15.3343×10-7 m2s-1 and the estimated magnitude of the mass-transfer coefficient (Kf) was 0.0346×10-9 m s-1 (temperature = 298 K, C0= 6 mgL-1). An ANN (artificial neural network) model applied to optimize and simulate the defluoridation procedure. Furthermore, continuous flow column reactor was conducted to investigate the practical applicability of composites in the defluoridation process. The Yoon-Nelson and the Thomas model exhibited excellent conformity with the breakthrough curves. Nanocellulose/PVA satisfactorily eliminated fluoride from its aqueous solution and can be considered as a suitable bio-sorbent for defluoridation.

Evaluation of In vivo Antimalarial Property of Nyctanthes arbor-tristis (Night Jasmine) Leaves.

BACKGROUND: Nyctanthes arbor-tristis (NAT) is an ornamental garden plant traditionally used for treating many diseases such as helminthiasis, arthritis, and malaria. AIMS: The aim of this study was to validate the ethnobotanical uses of the antimalarial activity of leaves of NAT by in vivo tests. MATERIALS AND METHODS: Leaves of NAT were identified and authenticated and phytoconstituents of NAT were identified. The antimalarial activity of NAT was studied in in vivo for its schizonticidal activity, repository activity, and curative tests in Swiss albino mice by using Plasmodium berghei (ANKA). STATISTICAL ANALYSIS USED: One-way ANOVA was done for comparison of different groups followed by post hoc analysis (Tukey-Kramer multiple comparison tests). Level of significance was at P < 0.05. RESULTS: The mean schizonticidal activity of NAT increased from 14.21 to 46.15 (P < 0.01) with doses ranging from 100 to 200 mg/kg compared to 67.29 with that of chloroquine (CQ). The repository activity with NAT doses 100-200 mg/kg increased from 12.91 to 42.85 (P < 0.01) compared to 78.79 in pyrimethamine 1.2 mg/kg/day. In Rane's test, there was chemosuppression in range of 55.50-65.02 (P < 0.01) with NAT in doses of 100-200 mg/kg compared to 74.15 with that of CQ 5 mg/kg. CONCLUSIONS: The antiplasmodial activity of NAT might be like that of artemisinin by producing oxidative stress mostly due to the iridoid glycosides. The active phytoconstituent(s) responsible may be tested individually or in combination both by in vitro and in vivo studies to identify the active chemical ingredient.

Microfluidic Protein Imaging Platform: Study of Tau Protein Aggregation and Alzheimer's Drug Response.

Tau protein aggregation is identified as one of the key phenomena associated with the onset and progression of Alzheimer's disease. In the present study, we performed on-chip confocal imaging of tau protein aggregation and tau-drug interactions using a spiral-shaped passive micromixing platform. Numerical simulations and experiments were performed in order to validate the performance of the micromixer design. We performed molecular modeling of adenosine triphosphate (ATP)-induced tau aggregation in order to successfully validate the concept of helical tau filament formation. Tau aggregation and native tau restoration were realized using an immunofluorescence antibody assay. The dose-response behavior of an Alzheimer's drug, methylthioninium chloride (MTC), was monitored on-chip for defining the optimum concentration of the drug. The proposed device was tested for reliability and repeatability of on-chip tau imaging. The amount of the tau protein sample used in our experiments was significantly less than the usage for conventional techniques, and the whole protein-drug assay was realized in less than two hours. We identified that intensity-based tau imaging could be used to study Alzheimer's drug response. In addition, it was demonstrated that cell-free, microfluidic tau protein assays could be used as potential on-chip drug evaluation tools for Alzheimer's disease.

Treatment of malachite green dye containing solution using bio-degradable Sodium alginate/NaOH treated activated sugarcane baggsse charcoal beads: Batch, optimization using response surface methodology and continuous fixed bed column study.

In this study, carbonized material was produced using sodium hydroxide treated Sugar cane bagasse (SB), and synthesized materials ware used to prepare Sodium Alginate/SBAC composite beads which were further used as an adsorbent to remove malachite green dye (MG) present in water. Physiochemical characteristics of composite beads were analyzed using FTIR, SEM, TGA, and BET. Adsorption equilibrium data showed excellent fit to the Freundlich model (R2 = 0.994) than to the Langmuir model (R2 = 0.925). Adsorption kinetics study indicated that the MG removal process would be better described by the pseudo-second-order kinetic model. The thermodynamic study suggested the spontaneous and endothermic nature of MG adsorption. By using response surface methodology, the optimum conditions for MG adsorption on composite beads were found to be 115.43 min, 0.3 g/L and pH 8 for contact time, adsorbent mass, and pH respectively and MG adsorption efficiency was 97.88%. The fixed-bed column data were evaluated using several kinetic models and among them, Thomas model showed the best agreement with investigation results. These results revealed that synthesized composite beads have a high affinity toward MG and it could be reasonable, eco-friendly adsorbent for dye removal from wastewater.

Detection of exon location in eukaryotic DNA using a fuzzy adaptive Gabor wavelet transform.

The existing model-independent methods for the detection of exons in DNA could not prove to be ideal as commonly employed fixed window length strategy produces spectral leakage causing signal noise The Modified-Gabor-wavelet-transform exploits a multiscale strategy to deal with the issue to some extent. Yet, no rule regarding the occurrence of small and large exons has been specified. To overcome this randomness, scaling-factor of GWT has been adapted based on a fuzzy rule. Due to the nucleotides' genetic code and fuzzy behaviors in DNA configuration, this work could adopt the fuzzy approach. Two fuzzy membership functions (large and small) take care of the variation in the coding regions. The fuzzy-based learning parameter adaptively tunes the scale factor for fast and precise prediction of exons. The proposed approach has an immense plus point of being capable of isolating detailed sub-regions in each exon efficiently proving its efficacy comparing with existing techniques.

Hereditary disease prediction in eukaryotic DNA: an adaptive signal processing approach.

Hereditary disease prediction in eukaryotic DNA using signal processing approaches is an incredible work in bioinformatics. Researchers of various fields are trying to put forth a noninvasive approach to forecast the disease-related genes. As diseased genes are more random than the healthy ones, in this work, a comparison of the diseased gene is made against the healthy ones. An adaptive signal processing method like functional link artificial neural network-based Levenberg-Marquardt filter has been proposed in this regard. For parameter upgradation, the algorithm is modified using particle swarm optimization. Here, disease genes are discriminated from healthy ones based on the magnitude of mean square error (MSE), which is calculated through the adaptive filter. The performance of the algorithm is inspected by computing some evaluation parameters. Since accuracy is the prime concern, authors in this work have taken an attempt to improve the accuracy level compared to the existing methods. Taking the reference gene as healthy, the overall process is accomplished by categorizing the diseased and healthy targets with MSE value at a threshold of 0.012. The proposed technique predicts the test gene sets successfully.

An integrated approach for identification of exon locations using recursive Gauss Newton tuned adaptive Kaiser window.

Identification of exon location in a DNA sequence has been considered as the most demanding and challenging research topic in the field of Bioinformatics. This work proposes a robust approach combining the Trigonometric mapping with Adaptive tuned Kaiser Windowing approach for locating the protein coding regions (EXONS) in a genetic sequence. For better convergence as well as improved accurateness, the side lobe height control parameter (ß) of Kaiser Window in the proposed algorithm is made adaptive to track the changing dynamics of the genetic sequence. This yields better tracking potential of the anticipated Adaptive Kaiser algorithm as it uses the recursive Gauss Newton tuning which in turn utilizes the covariance of the error signal to tune the ß factor which has been shown through numerous simulation results under a variety of practical test conditions. A detailed comparative analysis with the existing mapping schemes, windowing techniques, and other signal processing methods like SVD, AN, DFT, STDFT, WT, and ST has also been included in the paper to focus on the strength and efficiency of the proposed approach. Moreover, some critical performance parameters have been computed using the proposed approach to investigate the effectiveness and robustness of the algorithm. In addition to this, the proposed approach has also been successfully applied on a number of benchmark gene sets like Musmusculus, Homosapiens, and C. elegans, etc., where the proposed approach revealed efficient prediction of exon location in contrast to the other existing mapping methods.

What Drives Patient Choice: Preferences for Approaches to Surgical Treatments for Breast Cancer Beyond Traditional Clinical Benchmarks.

IMPORTANCE: Understanding what drives breast cancer (BC) patient's surgical decision-making and why, as survival continues to improve, are women continuing to choose mastectomy in increasing numbers. OBJECTIVE: We sought to understand better what drives patient choice in surgical decision-making regarding BC treatment options. DESIGN: We used a dynamic model, adaptive conjoint-based survey experiment, to assess multiple factors concurrently impacting patient choice, conducted from December 2016 to January 2017 using the Army of Women. SETTING: Army of Women, is a U.S.-based nation-wide registry of women, both healthy and previous BC patients. PARTICIPANTS: An e-mail invitation was sent to the AWOL's 108,933 members, with 1,233 signing up to participate and 858 responding (548 healthy, 310 previous BC). Two hundred thirty-nine BC patients who underwent treatment > 5 years were excluded due to potential recall bias and changes in BC treatment paradigms. All subjects who did not complete the adaptive conjoint-based survey were also excluded due to inability to calculate preferences. The final sample consisted of 522 healthy women and 71 previous BC patients. INTERVENTIONS OR EXPOSURES: Study of patient preference and decision drivers, without, interventions or exposures. MAIN OUTCOMES AND MEASURES: Shares of preferences for various surgical treatment options were calculated using the highest-ranked factors, by the importance that drove patient decision-making. RESULTS: Survey response rate was 69.5%. Among healthy women, the most important of the 9 factors in making a surgical choice were doctor's recommendation at 21.4% (SD, 13.6%) and overall survival (OS) at 20.5% (SD, 9.8%) while among previous BC patients, the most important factor was OS at 19% (SD, 9%) and doctor's recommendation at 17.2% (SD, 10.3%). CONCLUSION AND RELEVANCE: While OS accounted for the largest single driver of patient choice at ~20 %, it is notable that 80% of patient decision-making was driven by factors unrelated to survival such as cost, intensity and recovery time, and breast image. By understanding what drives choice, we can provide better patient-centric education and treatments.

Acetylation-mediated Siah2 stabilization enhances PHD3 degradation in Helicobacter pylori-infected gastric epithelial cancer cells.

Gastric epithelial cells infected with Helicobacter pylori acquire highly invasive and metastatic characteristics. The seven in absentia homolog (Siah)2, an E3 ubiquitin ligase, is one of the major proteins that induces invasiveness of infected gastric epithelial cells. We find that p300-driven acetylation of Siah2 at lysine 139 residue stabilizes the molecule in infected cells, thereby substantially increasing its efficiency to degrade prolyl hydroxylase (PHD)3 in the gastric epithelium. This enhances the accumulation of an oncogenic transcription factor hypoxia-inducible factor 1α (Hif1α) in H. pylori-infected gastric cancer cells in normoxic condition and promotes invasiveness of infected cells. Increased acetylation of Siah2, Hif1α accumulation, and the absence of PHD3 in the infected human gastric metastatic cancer biopsy samples and in invasive murine gastric cancer tissues further confirm that the acetylated Siah2 (ac-Siah2)-Hif1α axis is crucial in promoting gastric cancer invasiveness. This study establishes the importance of a previously unrecognized function of ac-Siah2 in regulating invasiveness of H. pylori-infected gastric epithelial cells.-Kokate, S. B., Dixit, P., Das, L., Rath, S., Roy, A. D., Poirah, I., Chakraborty, D., Rout, N., Singh, S. P., Bhattacharyya, A. Acetylation-mediated Siah2 stabilization enhances PHD3 degradation in Helicobacter pylori-infected gastric epithelial cancer cells.

Immunohistochemical evaluation of prime molecules in cervical lesions towards assessment of malignant potentiality.

OBJECTIVE: A comparative immunohistochemical evaluation of p63, CD105, and E-cadherin expression pattern in histopathologically confirmed normal cervical epithelium (NCM), dysplastic cervical epithelium (DYS) and squamous cell carcinoma (SCC) of uterine cervix towards assessing malignant potentiality of the precancerous condition. MATERIALS AND METHODS: The biopsies from cervical mucosa (normal, dysplasia, and cancer) were studied by routine hematoxylin and eosin (H and E) and by immunohistochemistry for p63, E-cadherin, and CD105 expression. The expressions of these molecules were assessed in a semiquantitative way by (i) counting p63 cell population and distribution, (ii) intensity scoring of E-cadherin along the expression path, and (iii) measuring CD105 expression density. RESULT: p63+ cells were highest in carcinomas followed by dysplasia and normal. An abrupt increase in CD105 expression was observed through change of normal to dysplasia and cancer. A decrease in membranous E-cadherin expression was noticed in the transformation from normal to precancer and cancers. CONCLUSION: The malignant potential of the dysplastic conditions is likely to be correlated with upregulation in p63 and CD105 expression and a simultaneous downregulation of membranous E-cadherin.

The value of open access and a patient centric approach to oral oncolytic utilization in the treatment of Chronic Myelogenous Leukemia: A U.S. perspective.

INTRODUCTION: Since the introduction of tyrosine kinase inhibitors (TKIs), the treatment of patients with chronic myelogenous leukemia (CML) has resulted in significant improvement in patient survival but at a higher pharmaceutical cost to payers. The recent introduction of generic imatinib presents an opportunity to lower pharmacy costs within a population that is growing due to improved survival. Recent literature has focused on the likely benefits to payers of step therapy through generic imatinib. Areas covered: This review provides a perspective that is broader than the evaluation of financial savings or narrowly defined health economic metrics by incorporating factors such as CML patient heterogeneity, including varying levels of disease progression risk, comorbidities and genetic mutation status, differences in TKI product profiles, clinical guideline recommendations, and the importance of individualized patient care. A focused literature review evaluating the real-world impact of utilization management programs is presented. Expert commentary: The findings indicate that payers can achieve substantial savings without the need to implement utilization management policies. Compromises in the ability to provide individualized patient care and unwanted economic consequences resulting from increased costs of disease progression, adverse events, and lack of response to treatment due to utilization management are summarized.

Inhibition of histone/lysine acetyltransferase activity kills CoCl2-treated and hypoxia-exposed gastric cancer cells and reduces their invasiveness.

Hypoxia enhances immortality and metastatic properties of solid tumors. Deregulation of histone acetylation has been associated with several metastatic cancers but its effect on hypoxic responses of cancer cells is not known. This study aimed at understanding the effectiveness of the hydrazinocurcumin, CTK7A, an inhibitor of p300 lysine/histone acetyltransferase (KAT/HAT) activity, in inducing apoptosis of gastric cancer cells (GCCs) exposed to cobalt chloride (CoCl2), a hypoxia-mimetic chemical, or 1% O2. Here, we show that CTK7A-induced hydrogen peroxide (H2O2) generation in CoCl2-exposed and invasive gastric cancer cells (GCCs) leads to p38 MAPK-mediated Noxa expression and thereafter, mitochondrial apoptotic events. Noxa induction in normal immortalized gastric epithelial cells after CTK7A and hypoxia-exposure is remarkably less in comparison to similarly-treated GCCs. Moreover, hypoxia-exposed GCCs, which have acquired invasive properties, become apoptotic after CTK7A treatment to a significantly higher extent than normoxic cells. Thus, we show the potential of CTK7A in sensitizing hypoxic and metastatic GCCs to apoptosis induction.