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Transcription factor p53, also known as tumor suppressor protein. Encoded by the TP53 gene, the guardian of genome p53 regulates many gene pathways. Nevertheless, the molecular mechanisms of p53 functioning have been known for a few decades, and the exact role of p53 in cancer therapy is unclear. Also, comprehensive literature on heterocycles as p53‐MDM2 protein‐protein interaction inhibitors is limited. This review covers the molecular mechanism for the p53‐MDM2 interaction and its inhibition by the heterocyclic small molecules. We hope the present comprehensive study will help to develop heterocycles as anticancer drugs that induce apoptosis in tumor cells. [ABSTRACT FROM AUTHOR]

IL‐17‐producing Th17 cells play an important role in pathogenesis of rheumatoid arthritis (RA). Aberrant immune activation due to an imbalance between Th17 and regulatory T (Treg) cells is associated with the development of RA and other autoimmune diseases. Targeting pathogenic Th17 cells and their associated molecules is emerging as a promising strategy to treat and reverse RA. Here, we demonstrate that IL‐3 inhibits the differentiation of Th17 cells and promotes the development of Treg cells in IL‐2‐dependent manner. In IL‐2 KO mice, we observed that IL‐3 has no effect on differentiation of both Th17 and Treg cells. In addition, IL‐3 decreases pathogenic IL‐17A+TNF‐α+, IL‐17A+IFN‐γ+ and IL‐23R+ Th17 cells, secretion of GM‐CSF and IFN‐γ, and osteoclastogenesis when presented in the culture together with Th17 polarizing cytokines. Mechanistically, IL‐3 regulates the development of Th17 cells through the inhibition of STAT3 phosphorylation. IL‐3 treatment significantly decreases the pathogenic Th17 cell responses and arthritic scores in the mouse model of RA. Importantly, IL‐3 inhibits the differentiation of human Th17 cells. Thus, our results suggest a novel therapeutic role of IL‐3 in the regulation of Th17 cell‐mediated pathophysiology of RA. [ABSTRACT FROM AUTHOR]

Summary: Group key management with privacy preserving and trust still remains a precarious and stimulating issue for securing multicast communications in an energy embarrassed large wireless ad‐hoc networks (WANETs). To address this, few researchers with the adaption of blockchain technology and practical usage of a privacy‐preserving smart contract as group controller made these group key agreements adaptable to WANET. However, proportionate to the increase in the size of the group, the processing load on the smart contract is also increasing, which made the capability of the smart contract could not work beyond a certain group size. Contemporary blockchain schemes suffer from various inherent shortcomings in their latency, scalability, and processing throughput. So, in this direction, we adopted blockchain sharding smart contract‐centric processing for making the key agreement adaptable to large WANETs. In this technique, we divide the large network into r sharded subnetworks with G1, G2, G3, ..., Gr as smart contract instances generated by group controller G, which acts as subgroup controllers to their respective shards using blockchain sharding technique. This protocol is shown secure under the assumptions elliptic curve decision Diffie–Hellman and group‐elliptic curve Diffie–Hellman. The performance analysis demonstrates that the proposed protocol is highly proficient than examined protocols for secure communication in large WANETs. [ABSTRACT FROM AUTHOR]

The Co doped Li0.5Fe2.5O4 ferrites are successfully prepared by using sol–gel synthetic process. The resulting nanosample is characterized by using XRD and SEM technique. The x‐ray diffraction (XRD) analysis studies clearly suggest the formation of single phase nanomaterials. The SEM analysis indicates the formation of uniform and fine grains like morphology in mixed‐metal oxides. The results of combustion synthesis elucidate that the fuel to oxidizer ratio is the most effective factor for the formation and surface morphology of mixed‐metal oxides. The synthesized Co doped Li0.5Fe2.5O4 ferrite is used for the adsorption studies of methyl orange dye by batch experiments. It is found from the adsorption studies that the removal percentage of Methyl orange is much better. Li0.5Fe2.5O4 particles are good adsorbent materials for removal of methyl orange dyes as compare to the Co doped Li0.5Fe2.5O4 nanopowder. However, the adsorption capacity of Li0.5Fe2.5O4 can be lower by doping with cobalt. [ABSTRACT FROM AUTHOR]

Aim: An immunoproteomic approach was followed to identify immunoreactive antigens of fish ectoparasite, Argulus siamensis with rohu (Labeo rohita) immune sera for screening of potential vaccine candidates. Materials and results: The whole adult Argulus antigen was run in 2D electrophoresis with IEF in 7 cm IPG strips of pH 4‐7 and SDS‐PAGE with 12% acrylamide concentration. Two parallel gels were run; one was stained with silver stain, and the other was Western blotted to nitrocellulose paper (NCP) and reacted with rohu anti‐A siamensis sera. Fourteen protein spots corresponding to the spots developed in NCP were picked from the silver‐stained gel and subjected to mass spectrometry in MALDI‐TOF/TOF. The MS/MS spectra were analysed in MASCOT software with taxonomy 'other metazoa' and the proteins identified based on similarity with the proteins from heterologous species. The gene ontology analysis revealed a majority of proteins being involved in binding activity in 'molecular function' and belonging to metabolic processes in 'biologic process' categories. The possibility of these proteins as vaccine candidates against Asiamensis is discussed in the paper. Conclusion: Three of the identified proteins namely, bromodomain‐containing protein, anaphase‐promoting complex subunit 5 and elongation factor‐2 could possibly serve as vaccine candidates against argulosis in carps. [ABSTRACT FROM AUTHOR]

Introduction: Organizational transformations have focused on creating and fulfilling value for customers, leveraging advanced technologies. Transforming public health (PH) faces an interesting challenge. The value created (preventive practices) to fulfill policy makers' desire to reduce healthcare costs is realized by several external partners with varying goals and is practiced by the public (value in use), which often places low priority on prevention. Methods: This paper uses value lens to argue that PH transformation strategy must align the goals of all stakeholders involved. This may include allowing partners and the public to contextualize the preventive practices to see the value in near term and as relevant. It also means extending the number of partners PH uses and helping them connect with the public to seek shared alignment in shared goals of value fulfillment and value‐in‐use. Results: Using lessons from Covid‐19 and PH experience with partners in four different sectors: business, healthcare, public and community, the paper illustrates how PH transformation strategy can be implemented going forward. Conclusions: We conclude the paper with five distinct directions for future research to create and sustain value using the framework of learning health systems. [ABSTRACT FROM AUTHOR]

We report on the tunable and enhanced dielectric properties of tungsten (W) incorporated gallium oxide (Ga2O3) polycrystalline electroceramics for energy and power electronic device applications. The W‐incorporated Ga2O3 (Ga2−2xWxO3, 0.00 ≤ x ≤ 0.20; GWO) compounds were synthesized by the high‐temperature solid‐state chemical reaction method by varying the W‐content. The fundamental aspects of the dielectric properties in correlation with the crystal structure, phase, and microstructure of the GWO polycrystalline compounds has been investigated in detail. A detailed study performed ascertains the W‐induced changes in the dielectric constant, loss tangent (tan δ) and ac conductivity. It was found that the dielectric constant increases with addition of W in the system as a function of temperature (25°C‐500°C). Frequency dependence (102‐106 Hz) of the dielectric constant follows the modified Debye model with a relaxation time of ∼20 to 90 μs and a spreading factor of 0.39 to 0.65. The dielectric constant of GWO is temperature independent almost until ∼300°C, and then increases rapidly in the range of 300°C to 500°C. W‐induced enhancement in the dielectric constant of GWO is fully evident in the frequency and temperature dependent dielectric studies. The frequency and temperature dependent tan δ reveals the typical behavior of relaxation loses in GWO. Small polaron hopping mechanism is evident in the frequency dependent electrical transport properties of GWO. The remarkable effect of W‐incorporation on the dielectric and electrical transport properties of Ga2O3 is explained by a two‐layer heterogeneous model consisting of thick grains separated by very thin grain boundaries along with the formation of a Ga2O3‐WO3 composite was able to account for the observed temperature and frequency dependent electrical properties in GWO. The results demonstrate that the structure, electrical and dielectric properties can be tailored by tuning W‐content in the GWO compounds. [ABSTRACT FROM AUTHOR]

The effects of sintering temperature on the structural and magnetic properties of polycrystalline nickel ferrite synthesized by the novel polyol method are investigated. The effects of heat treatment temperature on crystalline phases formation, microstructure, and magnetic properties of Ni ferrite are investigated by x‐ray diffraction (XRD), thermogravimetric, and differential thermal analysis, scanning electron microscopy, transmission electron microscopy, Fourier‐transform infrared spectroscopy (FT‐IR), and B‐H loop tracer technique. The XRD plot of the powder samples sintered at different temperature shows increase in the peak intensity values with respect to temperature of sintering thereby showing an increasing crystallinity of the samples with an increasing sintering temperature. FT‐IR spectra for sample sintered at 773 K shows two sharp bands on octahedral and tetrahedral sites. Scanning electron micrographs show spherical and uniform grains which is observed on sintering temperature 773 K. Particle size of nickel ferrite is in the range of 11–15 nm, and depends on the sintering temperature and sintering time. The saturation magnetization increased from 23.45 to 45.61 emu g−1 and coercivity increases from 327.27 to 1097.03 Oe with an increase in particle size. [ABSTRACT FROM AUTHOR]

Keywords: ciclosporin; Parthenium dermatitis; treatment EN ciclosporin Parthenium dermatitis treatment 134 136 3 01/28/21 20210201 NES 210201 I Parthenium hysterophorus i , a weed of the Compositae family, is the most common cause of airborne contact dermatitis in India.1 It is a chronic debilitating illness resulting in high morbidity. Ciclosporin, an anti-inflammatory and immunosuppressant, has been shown to be effective in two patients with I Parthenium i dermatitis.4 In this case series, we evaluated clinical efficacy and safety of ciclosporin in patients with parthenium dermatitis. Thus, ciclosporin appears to be an effective drug in treatment of patients with I Parthenium i dermatitis, particularly when corticosteroids and azathioprine are contraindicated. [Extracted from the article]

Vitiligo is a multifactorial acquired depigmenting disorder. Recent insights into the molecular mechanisms driving the gradual destruction of melanocytes in vitiligo will likely lead to the discovery of novel therapies, which need to be evaluated in animal models that closely recapitulate the pathogenesis of human vitiligo. In humans, vitiligo is characterized by a spontaneous loss of functional melanocytes from the epidermis, but most animal models of vitiligo are either inducible or genetically programmed. Here, we report that acquired depigmentation in water buffalo recapitulates molecular, histological, immunohistochemical, and ultrastructural changes observed in human vitiligo and hence could be used as a model to study vitiligo pathogenesis and facilitate the discovery and evaluation of therapeutic interventions for vitiligo. [ABSTRACT FROM AUTHOR]

ABSTRACT Aggregation is an irreversible form of protein complexation and often toxic to cells. The process entails partial or major unfolding that is largely driven by hydration. We model the role of hydration in aggregation using 'Dehydrons.' 'Dehydrons' are unsatisfied backbone hydrogen bonds in proteins that seek shielding from water molecules by associating with ligands or proteins. We find that the residues at aggregation interfaces have hydrated backbones, and in contrast to other forms of protein-protein interactions, are under less evolutionary pressure to be conserved. Combining evolutionary conservation of residues and extent of backbone hydration allows us to distinguish regions on proteins associated with aggregation (non-conserved dehydron-residues) from other interaction interfaces (conserved dehydron-residues). This novel feature can complement the existing strategies used to investigate protein aggregation/complexation. Proteins 2016; 84:254-266. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Purpose: This paper investigates, via magnetic modeling and Monte Carlo simulation, the ability to deliver proton beams to the treatment zone inside a split-bore MRI-guided proton therapy system. Methods: Field maps from a split-bore 1 T MRI-Linac system are used as input to GEANT4 Monte Carlo simulations which model the trajectory of proton beams during their paths to the isocenter of the treatment area. Both inline (along the MRI bore) and perpendicular (through the split-bore gap) orientations are simulated. Monoenergetic parallel and diverging beams of energy 90, 195, and 300 MeV starting from 1.5 and 5 m above isocenter are modeled. A phase space file detailing a 2D calibration pattern is used to set the particle starting positions, and their spatial location as they cross isocenter is recorded. No beam scattering, collimation, or modulation of the proton beams is modeled. Results: In the inline orientation, the radial symmetry of the solenoidal style fringe field acts to rotate the protons around the beam's central axis. For protons starting at 1.5 m from isocenter, this rotation is 19° (90 MeV) and 9.8° (300 MeV). A minor focusing toward the beam's central axis is also seen, but only significant, i.e., 2 mm shift at 150 mm off-axis, for 90 MeV protons. For the perpendicular orientation, the main MRI field and near fringe field act as the strongest to deflect the protons in a consistent direction. When starting from 1.5 m above isocenter shifts of 135 mm (90 MeV) and 65 mm (300 MeV) were observed. Further to this, off-axis protons are slightly deflected toward or away from the central axis in the direction perpendicular to the main deflection direction. This leads to a distortion of the phase space pattern, not just a shift. This distortion increases from zero at the central axis to 10 mm (90 MeV) and 5 mm (300 MeV) for a proton 150 mm off-axis. In both orientations, there is a small but subtle difference in the deflection and distortion pattern between protons fired parallel to the beam axis and those fired from a point source. This is indicative of the 3D spatially variant nature of the MRI fringe field. Conclusions: For the first time, accurate magnetic and Monte Carlo modeling have been used to assess the transport of generic proton beams toward a 1 T split-bore MRI. Significant rotation is observed in the inline orientation, while more complex deflection and distortion are seen in the perpendicular orientation. The results of this study suggest that due to the complexity and energy-dependent nature of the magnetic deflection and distortion, the pencil beam scanning method will be the only choice for delivering a therapeutic proton beam inside a potential MRI-guided proton therapy system in either the inline or perpendicular orientation. Further to this, significant correction strategies will be required to account for the MRI fringe fields. [ABSTRACT FROM AUTHOR]

Contents The objective of this study was to investigate the effect of newly developed soya milk Tris ( SMT)-based phytoextender as an alternative to egg yolk Tris ( EYT) extender used for cryopreservation of buffalo ( Bubalus bubalis) spermatozoa on apoptosis. Fresh buffalo semen (control without dilution) was cryopreserved in conventional EYT (20% egg yolk v/v in Tris) and SMT (25% soya milk v/v in Tris) extender and used for the assessment of expression of apoptotic proteins. Proteins extracted from a total number of nine ejaculates from three individual buffalo bulls chosen at random were separated using SDS-PAGE followed by immunoblotting against caspase-8, caspase-9, caspase-3, poly(ADP-ribose)polymerase ( PARP), cytochrome c and apoptosis inducing factor ( AIF). In addition, fluorescence microscopy was used for the detection of mitochondrial membrane potential (JC-1 assay) and apoptotic cells (annexin V-FITC/PI assay). The results obtained clearly indicate the significant (p < 0.05) reduction in the expression of caspase-3 (27 kDa), caspase-8 (53 kDa), caspase-9 (50 kDa) precursor and cytochrome c (17 kDa) in semen cryopreserved in SMT extender in comparison with EYT extender. A non-significant (p > 0.05) reduction in expression of PARP-DNA-binding subunit (24 kDa) was observed in SMT extender. No expression of AIF was found in cryopreserved semen samples. A significant (p < 0.05) increase in the mean percentage of cells having high mitochondrial membrane potential and a non-significant (p > 0.05) decrease in late apoptotic cells (AN+/PI+) was observed in SMT extender when compared to EYT extender. The results demonstrated that cryopreservation of buffalo semen in SMT-based phytoextender can replace the traditional egg yolk extenders as it reduces the expression of apoptotic proteins maintaining high mitochondrial membrane potential and gives better protection to sperms in terms of its non-animal origin. [ABSTRACT FROM AUTHOR]

There is emerging evidence that stem cells can rejuvenate damaged cells by mitochondrial transfer. Earlier studies show that epithelial mitochondrial dysfunction is critical in asthma pathogenesis. Here we show for the first time that Miro1, a mitochondrial Rho- GTPase, regulates intercellular mitochondrial movement from mesenchymal stem cells ( MSC) to epithelial cells ( EC). We demonstrate that overexpression of Miro1 in MSC ( MSCmiroHi) leads to enhanced mitochondrial transfer and rescue of epithelial injury, while Miro1 knockdown ( MSCmiroLo) leads to loss of efficacy. Treatment with MSCmiroHi was associated with greater therapeutic efficacy, when compared to control MSC, in mouse models of rotenone (Rot) induced airway injury and allergic airway inflammation ( AAI). Notably, airway hyperresponsiveness and remodeling were reversed by MSCmiroHi in three separate allergen-induced asthma models. In a human in vitro system, MSCmiroHi reversed mitochondrial dysfunction in bronchial epithelial cells treated with pro-inflammatory supernatant of IL-13-induced macrophages. Anti-inflammatory MSC products like NO, TGF-β, IL-10 and PGE2, were unchanged by Miro1 overexpression, excluding non-specific paracrine effects. In summary, Miro1 overexpression leads to increased stem cell repair. [ABSTRACT FROM AUTHOR]

Plant-based extracts present a large source of natural immune modulators, many of which have been used in traditional medicine for centuries. Recent research efforts have identified plant extracts as potential modulators of Toll-like receptors (TLRs), the first responders in immunological defenses in normal and disease conditions. This review aims to provide a comprehensive discussion of the modulatory effects of plant-based extracts on TLR expression, signaling, and activation. We organized the review by extraction solvent and plant part showing how they impacted the TLRs. The phytochemical components of the extracts discovered to enable these effects are diverse and vary based on the plant part. The role of the extraction solvent and differences between the different phytochemical components, such as phenolics and polysaccharides, are discussed. Plant extracts hold promising treatments for controlling inflammation and, conversely, for stimulating the immune response. Further research is needed to identify bioactive components of the extracts, mechanisms of their action, and in vivo pharmacological effects using appropriate disease models to ultimately adapt the findings for clinical use. Copyright © 2012 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Purpose: Intensity-modulated proton therapy (IMPT) using spot scanned proton beams relies on the delivery of a large number of beamlets to shape the dose distribution in a highly conformal manner. The authors have developed a 3D system based on liquid scintillator to measure the spatial location, intensity, and depth of penetration (energy) of the proton beamlets in near real-time. Methods: The detector system consists of a 20 × 20 × 20 cc liquid scintillator (LS) material in a light tight enclosure connected to a CCD camera. This camera has a field of view of 25.7 by 19.3 cm and a pixel size of 0.4 mm. While the LS is irradiated, the camera continuously acquires images of the light distribution produced inside the LS. Irradiations were made with proton pencil beams produced with a spot-scanning nozzle. Pencil beams with nominal ranges in water between 9.5 and 17.6 cm were scanned to irradiate an area of 10 × 10 cm square on the surface of the LS phantom. Image frames were acquired at 50 ms per frame. Results: The signal to noise ratio of a typical Bragg peak was about 170. Proton range measured from the light distribution produced in the LS was accurate to within 0.3 mm on average. The largest deviation seen between the nominal and measured range was 0.6 mm. Lateral position of the measured pencil beam was accurate to within 0.4 mm on average. The largest deviation seen between the nominal and measured lateral position was 0.8 mm; however, the accuracy of this measurement could be improved by correcting light scattering artifacts. Intensity of single proton spots were measured with precision ranging from 3 % for the smallest spot intensity (0.005 MU) to 0.5 % for the largest spot (0.04 MU). Conclusions: Our LS detector system has been shown to be capable of fast, submillimeter spatial localization of proton spots delivered in a 3D volume. This system could be used for beam range, intensity and position verification in IMPT. [ABSTRACT FROM AUTHOR]

In this article, we address the problem of allocating an additional cell tower (or a set of towers) to an existing cellular network, maximizing the call completion probability. Our approach is derived from the adaptive spatial sampling problem using kriging, capitalizing on spatial correlation between cell phone signal strength data points and accounting for terrain morphology. Cell phone demand is reflected by population counts in the form of weights. The objective function, which is the weighted call completion probability, is highly nonlinear and complex (nondifferentiable and discontinuous). Sequential and simultaneous discrete optimization techniques are presented, and heuristics such as simulated annealing and Nelder–Mead are suggested to solve our problem. The adaptive spatial sampling problem is defined and related to the additional facility location problem. The approach is illustrated using data on cell phone call completion probability in a rural region of Erie County in western New York, and accounts for terrain variation using a line-of-sight approach. Finally, the computational results of sequential and simultaneous approaches are compared. Our model is also applicable to other facility location problems that aim to minimize the uncertainty associated with a customer visiting a new facility that has been added to an existing set of facilities. [ABSTRACT FROM AUTHOR]

Background: One of the most common esthetic concerns associated with periodontal tissues is gingival recession. There are multiple periodontal plastic surgery approaches documented in the literature for the treatment of such defects. With the tremendous advances being made in periodontal science and technology, tissue engineering could be considered among the latest exciting techniques for recession management. Methods: In this split-mouth, controlled, double-masked clinical case series, 20 sites from 10 patients with Miller Class I or 1I recessions affecting canines or premolars in the maxillary arch were selected. One tooth in each patient was randomized to receive either a subepithelial connective tissue graft (SCTG) (control group) or an acellular dermal matrix allograft (ADMA) seeded with autologous gingival fibroblasts (test group) under a coronally positioned flap. Clinical parameters, including recession depth, probing depth, clinical attachment level, width of keratinized tissue, attached gingiva, and plaque scores, were recorded by a calibrated examiner at baseline and 3 and 6 months. The inflammation of grafted sites was scored, and the healing time was calculated. The final esthetic outcome of treated sites was assessed by the root coverage esthetic score at the end of 6 months. Results: There were no significant differences between test and control sites for all measured clinical parameters. However, the test sites demonstrated less inflammation in the early postoperative period. Conclusion: Within the limits of this case series, the results indicate that an ADMA seeded with autologous gingival fibroblasts by tissue-engineering technology may be explored as a substitute to an SCTG for the treatment of Miller Class I and II recession defects. [ABSTRACT FROM AUTHOR]

Four-dimensional (4D) radiotherapy is the explicit inclusion of the temporal changes in anatomy during the imaging, planning, and delivery of radiotherapy. One key component of 4D radiotherapy planning is the ability to automatically (“auto”) create contours on all of the respiratory phase computed tomography (CT) datasets comprising a 4D CT scan, based on contours manually drawn on one CT image set from one phase. A tool that can be used to automatically propagate manually drawn contours to CT scans of other respiratory phases is deformable image registration. The purpose of the current study was to geometrically quantify the difference between automatically generated contours with manually drawn contours. Four-DCT data sets of 13 patients consisting of ten three-dimensional CT image sets acquired at different respiratory phases were used for this study. Tumor and normal tissue structures [gross tumor volume (GTV), esophagus, right lung, left lung, heart and cord] were manually drawn on each respiratory phase of each patient. Large deformable diffeomorphic image registration was performed to map each CT set from the peak-inhale respiration phase to the CT image sets corresponding with subsequent respiration phases. The calculated displacement vector fields were used to deform contours automatically drawn on the inhale phase to the other respiratory phase CT image sets. The code was interfaced to a treatment planning system to view the resulting images and to obtain the volumetric, displacement, and surface congruence information; 692 automatically generated structures were compared with 692 manually drawn structures. The auto- and manual methods showed similar trends, with a smaller difference observed between the GTVs than other structures. The auto-contoured structures agree with the manually drawn structures, especially in the case of the GTV, to within published inter-observer variations. For the GTV, fractional volumes agree to within 0.2±0.1, center of mass displacements agree to within 0.5±1.5 mm, and agreement of surface congruence is 0.0±1.1 mm. The surface congruence between automatic and manual contours for the GTV, heart, left lung, right lung and esophagus was less than 5 mm in 99%, 94%, 94%, 91% and 89%, respectively. Careful assessment of the performance of automatic algorithms is needed in the presence of 4D CT artifacts. [ABSTRACT FROM AUTHOR]

Four-dimensional (4D) computed tomography (CT) imaging has found increasing importance in the localization of tumor and surrounding normal structures throughout the respiratory cycle. Based on such tumor motion information, it is possible to identify the appropriate phase interval for respiratory gated treatment planning and delivery. Such a gating phase interval is determined retrospectively based on tumor motion from internal tumor displacement. However, respiratory-gated treatment is delivered prospectively based on motion determined predominantly from an external monitor. Therefore, the simulation gate threshold determined from the retrospective phase interval selected for gating at 4D CT simulation may not correspond to the delivery gate threshold that is determined from the prospective external monitor displacement at treatment delivery. The purpose of the present work is to establish a relationship between the thresholds for respiratory gating determined at CT simulation and treatment delivery, respectively. One hundred fifty external respiratory motion traces, from 90 patients, with and without audio-visual biofeedback, are analyzed. Two respiratory phase intervals, 40%–60% and 30%–70%, are chosen for respiratory gating from the 4D CT-derived tumor motion trajectory. From residual tumor displacements within each such gating phase interval, a simulation gate threshold is defined based on (a) the average and (b) the maximum respiratory displacement within the phase interval. The duty cycle for prospective gated delivery is estimated from the proportion of external monitor displacement data points within both the selected phase interval and the simulation gate threshold. The delivery gate threshold is then determined iteratively to match the above determined duty cycle. The magnitude of the difference between such gate thresholds determined at simulation and treatment delivery is quantified in each case. Phantom motion tests yielded coincidence of simulation and delivery gate thresholds to within 0.3%. For patient data analysis, differences between simulation and delivery gate thresholds are reported as a fraction of the total respiratory motion range. For the smaller phase interval, the differences between simulation and delivery gate thresholds are 8±11% and 14±21% with and without audio-visual biofeedback, respectively, when the simulation gate threshold is determined based on the mean respiratory displacement within the 40%–60% gating phase interval. For the longer phase interval, corresponding differences are 4±7% and 8±15% with and without audio-visual biofeedback, respectively. Alternatively, when the simulation gate threshold is determined based on the maximum average respiratory displacement within the gating phase interval, greater differences between simulation and delivery gate thresholds are observed. A relationship between retrospective simulation gate threshold and prospective delivery gate threshold for respiratory gating is established and validated for regular and nonregular respiratory motion. Using this relationship, the delivery gate threshold can be reliably estimated at the time of 4D CT simulation, thereby improving the accuracy and efficiency of respiratory-gated radiation delivery. [ABSTRACT FROM AUTHOR]

In 2005, breast cancer will kill approximately 40,410 women in the U.S., and pancreatic cancer will kill approximately 31,800 men and women in the U.S. Clinical examination and mammography, the currently accepted breast cancer screening methods, miss almost half of breast cancers in women younger than 40 years, approximately one-quarter of cancers in women aged 40-49 years, and one-fifth of cancers in women over 50 years old. Pancreatic cancer progresses rapidly, with only 1% of patients surviving more than 5 years after diagnosis. However, if the disease is diagnosed when it is localized, the 5-year survival is approximately 20%. It would be beneficial to detect breast cancer and pancreatic cancer at the earliest possible stage, when multimodal therapy with surgery, radiotherapy, and chemotherapy have the greatest chance of prolonging survival. Human estrogen receptor-positive breast cancer cells typically display elevated levels of Myc protein due to overexpression of MYC mRNA, elevated cyclin D1 protein due to overexpression of CCND1 mRNA, and elevated insulin-like growth factor 1 receptor (IGF1R) due to overexpression of IGF1R mRNA. We hypothesized that scintigraphic detection of MYC or CCND1 peptide nucleic acid (PNA) probes with an IGF1 peptide loop on the C-terminus, and a Tc-99m-chelator peptide on the N-terminus, could measure levels of MYC or CCND1 mRNA noninvasively in human IGF1Roverexpressing MCF7 breast cancer xenografts in immunocompromised mice. Similarly, human pancreatic cancer cells typically display elevated levels of KRAS mRNA and elevated IGF1R. Hence, we also hypothesized that a KRAS Tc- 99m-chelator PNA-peptide probe could detect overexpression of KRAS mRNA in pancreatic cancer xenografts by scintigraphic imaging, or by positron emission tomography (PET) with a KRAS Cu-64-chelator PNA-peptide. Human MCF7 breast cancer xenografts in immunocompromised mice were imaged scintigraphically 4-24 h after tail-vein administration of MYC or CCND1 Tc- 99m-chelator PNA-peptides, but not after administration of mismatch controls. Similarly, human Panc-1 pancreatic cancer cells xenografts were imaged scintigraphically 4 and 24 h after tail-vein administration of a KRAS Tc-99mchelator PNA-peptide, and AsPC1 xenografts were imaged by PET 4 and 24 h after tail-vein adminstration of a KRAS Cu-64-chelator PNA-peptide. The radioprobes distributed normally to the kidneys, livers, tumors, and other tissues. External molecular imaging of oncogene mRNAs in solid tumors with radiolabel-PNA-peptide chimeras might in the future provide additional genetic characterization of pre-invasive and invasive breast cancers. [ABSTRACT FROM AUTHOR]

Thermal trauma causes tissue damage by membrane destabilization and energy depletion at the cellular level, resulting in tissue necrosis and inflammation leading to delayed cell death. One therapeutic approach is to block the immediate triggering of the inflammatory cascade that results in prolonged hypermetabolic responses and immune dysfunction while promoting the expression of growth factors. In the present study, we determined hepatic gene expression responses to insulin-like growth factors-i (IGF-I) gene transfer to burned rats using high-density DNA microarray assays. The expression of 123 out of ~8,800 genes assyed (1.4% of total) were significantly altered. Of these, 42 genes were altered irrespective of treatment by burn trauma ( p < 0.05). Changes in gene expression were confirmed by measuring mRNA levels using reverse transcription-polymerase chain reaction and protein levels by Western blot assays. DNA microarray analyses showed two major mechanisms that mediated beneficial outcomes after IGF-I gene transfer in the burned rat livers. These mechanisms were the stimulation of IGF binding protein potentiation of peripheral IGF-I and the inhibition of the burn-augmented pro-apoptotic and oxidative mitochondrial metabolites stimulated by thermal trauma. [ABSTRACT FROM AUTHOR]

Severe burns cause not only skin injury but several marked systemic derangements. During wound healing, matrix metalloproteinases (MMPs) and the tissue inhibitors of metalloproteinases play an important role in tissue regeneration and remodeling processes. Therefore, in the present study, we determined the serum levels of MMPs and tissue inhibitor of metalloproteinase-1 in burn patients over time. Serum samples from 12 severely burned children (mean age 7.9 ± 2.5 years) with >40% total body surface area burns were obtained within 0.5 hours, 3, 7, and 21 days after injury. Pro-MMP-1, MMP-3, MMP-9, and tissue inhibitor of metalloproteinase-1 serum levels were assayed by enzyme-linked immunoassay and compared to normal healthy volunteers. Two-way analysis of variance and Bonferroni's test were used for statistical analysis. Pro-MMP-1 levels in the serum were significantly elevated by the seventh day after burn. MMP-3 and MMP-9 levels showed significant increases by day 3 and 21 compared to normals, respectively. Tissue inhibitor of metalloproteinase-1 levels did not change with time after burn but were significantly higher by 3 days after burn compared to normal serum. In conclusion, changes in MMPs and tissue inhibitor of metalloproteinase-1 occur in burn patients and those changes may be a mechanism beneficial to wound healing. (WOUND REP REG 2003;11:177–180). [ABSTRACT FROM AUTHOR]

Summary The INO2 gene of Saccharomyces cerevisiae is required for expression of most of the phospholipid biosynthetic genes. INO2 expression is regulated by a complex cascade that includes autoregulation, Opi1p-mediated repression and Ume6p-mediated activation. To screen for mutants with altered INO2 expression directly, we constructed an INO2-HIS3 reporter that provides a plate assay for INO2 promoter activity. This reporter was used to isolate mutants (dim1 ) that fail to repress expression of the INO2 gene in an otherwise wild-type strain. The dim1 mutants contain mutations in the OPI1 gene. To define further the mechanism for Ume6p regulation of INO2 expression, we isolated suppressors (rum1 , 2 , 3 ) of the ume6 Δ mutation that overexpress the INO2-HIS3 gene. Two of the rum mutant groups contain mutations in the OPI1 and SIN3 genes showing that opi1 and sin3 mutations are epistatic to the ume6 Δ mutation. These results are surprising given that Ume6p, Sin3p and Rpd3p are known to form a complex that represses the expression of a diverse set of yeast genes. This prompted us to examine the effect of sin3 Δ and rpd3 Δ mutants on INO2-cat expression. Surprisingly, the sin3 Δ allele overexpressed INO2-cat , whereas the rpd3 Δ mutant had no effect. We also show that the UME6 gene does not affect the expression of an OPI1-cat reporter. This suggests that Ume6p does not regulate INO2 expression indirectly by regulating OPI1 expression. [ABSTRACT FROM AUTHOR]

We tested the hypothesis that 21 days of intermittent hypoxia (IH) increases the tolerance of the spontaneously beating guinea-pig double atria preparation to acute in-vitro hypoxia, and reduces cardiac stress protein expression. A total of 28 guinea-pigs were divided into four groups: (i) IH; (ii) IH + in-vitro hypoxia (IH + IV); (iii) control (CON); (iv) control + in-vitro hypoxia (CON + IV). The IH animals were exposed to 8% O2/0.3% CO2 for 12 h day–1 for 21 days. Normoxic controls were exposed to room air for the same duration. Acute in-vitro hypoxia (20, 10, 5 and 0% O2 in 5% CO2) was introduced into the atrial preparation. Heat shock protein (Hsp) 70 and Hsp90 content were determined by Western blotting. Intermittent hypoxia groups demonstrated typical responses to chronic hypoxic exposure, characterized by significantly (P < 0.05) lower body weights, reduced growth rates and increased heart weight/body weight ratios. In the CON + IV group, in-vitro hypoxia reduced heart rate (20% O2, –30 ± 8 beats min–1; 10% O2, –34 ± 8 beats min–1; 5% O2, –37 ± 9 beats min–1 and 0% O2, –51 ± 9* beats min–1: *P < 0.05 vs. 20% O2). At 0% O2, the decrease in the rate response was significantly attenuated in the IH + IV (–30 ± 8 beats min–1; n=10) compared with the CON + IV (–51 ± 9 beats min–1; n=10). IH significantly reduced atrial Hsp70 and Hsp90 expression, however, levels of both proteins were unchanged in the ventricle. Furthermore, Hsp90 and to a lesser degree Hsp70 in the atria remained suppressed following in-vitro hypoxia in the IH group. Our results show that the increased resistance of the isolated atria to anoxia following IH may contribute to the concomitant reductions in basal and hypoxia-induced Hsp expression as the overall stress response is reduced. [ABSTRACT FROM AUTHOR]