A Simplified Approach for Determination of Inflection Points of Flattening Filter-Free Photon Beam Using In-House Developed Software and Derivation of Reference Levels.

Aim: This article aimed to present the salient features of the in-house developed Java program for the determination of inflection point and dosimetric parameters of flattening filter-free (FFF) photon beam. Reference levels for the dosimetric parameters of the FFF photon beams were also presented. Materials and Methods: Beam profiles of 6 MV FFF and 10 MV FFF photon beams for a collimator setting of 20 cm × 20 cm measured at 10 cm depth in an isocentric setup acquired from various institutions were analyzed using an in-house developed Java program and manual method. The values of reference dose value (RDV), field size, penumbra, and degree of un-flatness (defined as the lateral separation between 90% [X90%], 75% [X75%], and 60% [X60%] dose points on the profile) were calculated and compared. The reference values of field size, penumbra, and degree of un-flatness were also determined for Varian and Elekta medical electron linear accelerators (LINACs). Results: The maximum differences for RDV determined using the Java method and manual method are 2.4% and 2.7% for 6 and 10 MV FFF photon beams, respectively. The maximum difference between the values of field size, penumbra, and degree of un-flatness determined using Java and manual methods is within 1.3 mm. The reference values of field size and penumbra for Varian LINACs are 19.94 ± 0.10 cm and 0.83 ± 0.08 cm (6 MV FFF) and 19.95 ± 0.10 cm and 0.83 ± 0.08 cm (10 MV FFF). Similarly, the reference values of field size and penumbra for Elekta LINACs are 20.02 ± 0.09 cm and 0.94 ± 0.12 cm (6 MV FFF) and 20.03 ± 0.11 cm and 0.97 ± 0.16 cm (10 MV FFF). Conclusions: A software program was developed in Java for analyzing the beam profiles of FFF photon beams. The results of Java-derived values of dosimetric parameters of FFF photon beams were found in good agreement with the values determined using the manual method. The reference values of these parameters were also derived and quoted using a large cohort of the data.

Probing Gluon Spin-Momentum Correlations in Transversely Polarized Protons through Midrapidity Isolated Direct Photons in p

Studying spin-momentum correlations in hadronic collisions offers a glimpse into a three-dimensional picture of proton structure. The transverse single-spin asymmetry for midrapidity isolated direct photons in p^{↑}+p collisions at sqrt[s]=200 GeV is measured with the PHENIX detector at the Relativistic Heavy Ion Collider (RHIC). Because direct photons in particular are produced from the hard scattering and do not interact via the strong force, this measurement is a clean probe of initial-state spin-momentum correlations inside the proton and is in particular sensitive to gluon interference effects within the proton. This is the first time direct photons have been used as a probe of spin-momentum correlations at RHIC. The uncertainties on the results are a 50-fold improvement with respect to those of the one prior measurement for the same observable, from the Fermilab E704 experiment. These results constrain gluon spin-momentum correlations in transversely polarized protons.

Nuclear Dependence of the Transverse Single-Spin Asymmetry in the Production of Charged Hadrons at Forward Rapidity in Polarized p+p, p+Al, and p+Au Collisions at sqrt[s_{NN}]=200 GeV.

We report on the nuclear dependence of transverse single-spin asymmetries (TSSAs) in the production of positively charged hadrons in polarized p^{↑}+p, p^{↑}+Al, and p^{↑}+Au collisions at sqrt[s_{NN}]=200 GeV. The measurements have been performed at forward rapidity (1.4<η<2.4) over the range of transverse momentum (1.8

Treatment of glioblastoma using multicomponent silica nanoparticles.

Glioblastomas (GBMs) remain highly lethal. This partially stems from the presence of brain tumor initiating cells (BTICs), a highly plastic cellular subpopulation that is resistant to current therapies. In addition to resistance, the blood-brain barrier limits the penetration of most drugs into GBMs. To effectively deliver a BTIC-specific inhibitor to brain tumors, we developed a multicomponent nanoparticle, termed Fe@MSN, which contains a mesoporous silica shell and an iron oxide core. Fibronectin-targeting ligands directed the nanoparticle to the near-perivascular areas of GBM. After Fe@MSN particles deposited in the tumor, an external low-power radiofrequency (RF) field triggered rapid drug release due to mechanical tumbling of the particle resulting in penetration of high amounts of drug across the blood-brain tumor interface and widespread drug delivery into the GBM. We loaded the nanoparticle with the drug 1400W, which is a potent inhibitor of the inducible nitric oxide synthase (iNOS). It has been shown that iNOS is preferentially expressed in BTICs and is required for their maintenance. Using the 1400W-loaded Fe@MSN and RF-triggered release, in vivo studies indicated that the treatment disrupted the BTIC population in hypoxic niches, suppressed tumor growth and significantly increased survival in BTIC-derived GBM xenografts.

Synthesis, characterization and application of green seaweed mediated silver nanoparticles (AgNPs) as antibacterial agents for water disinfection.

A simple and eco-friendly method for the synthesis of hybrid bead silver nanoparticles (AgNPs) employing the aqueous extract derived from natural and renewable source namely tropical benthic green seaweed Ulva flexuosa was developed. This route involves the reduction of Ag+ ions anchored onto macro porous methacrylic acid copolymer beads to AgNPs for employing them as antibacterial agents for in vitro water disinfection. The seaweed extract itself acts as a reducing and stabilizing agent and requires no additional surfactant or capping agent for forming the AgNPs. The nanoparticles were analyzed using high-resolution transmission electron microscopy, UV-Vis spectroscopy, Fourier transform infrared spectroscopy, scanning electron microscopy, energy dispersive X-ray analysis and inductively coupled plasma optical emission spectroscopy. The study elucidates that such biologically synthesized AgNPs exhibit potential antibacterial activity against two Gram positive (Bacillus subtilis, Staphylococcus aureus) and two Gram-negative (Escherichia coli, Pseudomonas aeruginosa) bacterial strains tested. The bacterial count in treated water was reduced to zero for all the strains. Atomic force microscopy was performed to confirm the pre- and post-state of the bacteria with reference to their treatment with AgNPs. Attributes like facile environment-friendly procedure, stability and high antibacterial potency propel the consideration of these AgNPs as promising antibacterial entities.

Measurements of Multiparticle Correlations in d+Au Collisions at 200, 62.4, 39, and 19.6 GeV and p+Au Collisions at 200 GeV and Implications for Collective Behavior.

Recently, multiparticle-correlation measurements of relativistic p/d/^{3}He+Au, p+Pb, and even p+p collisions show surprising collective signatures. Here, we present beam-energy-scan measurements of two-, four-, and six-particle angular correlations in d+Au collisions at sqrt[s_{NN}]=200, 62.4, 39, and 19.6 GeV. We also present measurements of two- and four-particle angular correlations in p+Au collisions at sqrt[s_{NN}]=200 GeV. We find the four-particle cumulant to be real valued for d+Au collisions at all four energies. We also find that the four-particle cumulant in p+Au has the opposite sign as that in d+Au. Further, we find that the six-particle cumulant agrees with the four-particle cumulant in d+Au collisions at 200 GeV, indicating that nonflow effects are subdominant. These observations provide strong evidence that the correlations originate from the initial geometric configuration, which is then translated into the momentum distribution for all particles, commonly referred to as collectivity.

Nuclear Dependence of the Transverse-Single-Spin Asymmetry for Forward Neutron Production in Polarized p+A Collisions at sqrt[s_{NN}]=200 GeV.

During 2015, the Relativistic Heavy Ion Collider (RHIC) provided collisions of transversely polarized protons with Au and Al nuclei for the first time, enabling the exploration of transverse-single-spin asymmetries with heavy nuclei. Large single-spin asymmetries in very forward neutron production have been previously observed in transversely polarized p+p collisions at RHIC, and the existing theoretical framework that was successful in describing the single-spin asymmetry in p+p collisions predicts only a moderate atomic-mass-number (A) dependence. In contrast, the asymmetries observed at RHIC in p+A collisions showed a surprisingly strong A dependence in inclusive forward neutron production. The observed asymmetry in p+Al collisions is much smaller, while the asymmetry in p+Au collisions is a factor of 3 larger in absolute value and of opposite sign. The interplay of different neutron production mechanisms is discussed as a possible explanation of the observed A dependence.

One-pot synthesis of nanochain particles for targeting brain tumors.

To synthesize multi-component nanochains, we developed a simple 'one-pot' synthesis, which exhibited high yield and consistency. The nanochains particles consist of parent nanospheres chemically linked into a higher-order, chain-like assembly. The one-pot synthesis is based on the addition of two types of parent nanospheres in terms of their surface chemical functionality (e.g., decorated with PEG-NH2 or PEG-COOH). By reacting the two types of parent nanospheres at a specific ratio (∼2 : 1) for a short period of time (∼30 min) under rigorous stirring, nanochains were formed. For example, we show the synthesis of iron oxide nanochains with lengths of about 125 nm consisting of 3-5 constituting nanospheres. The chain-like shaped nanoparticle possessed a unique ability to target and rapidly deposit on the endothelium of glioma sites via vascular targeting. To target and image invasive brain tumors, we used iron oxide nanochains with the targeting ligand being the fibronectin-targeting peptide CREKA. Overexpression of fibronectin is strongly associated with the perivascular regions of glioblastoma multiforme and plays a critical role in migrating and invasive glioma cells. In mice with invasive glioma tumors, 3.7% of the injected CREKA-targeted nanochains was found in gliomas within 1 h. Notably, the intratumoral deposition of the nanochain was ∼2.6-fold higher than its spherical variant. Using MR imaging, the precise targeting of nanochains to gliomas provided images with the exact topology of the disease including their margin of infiltrating edges and distant invasive sites.

Nrf2-driven TERT regulates pentose phosphate pathway in glioblastoma.

Given the involvement of telomerase activation and dysregulated metabolism in glioma progression, the connection between these two critical players was investigated. Pharmacological inhibition of human Telomerase reverse transcriptase (hTERT) by Costunolide induced glioma cell apoptosis in a reactive oxygen species (ROS)-dependent manner. Costunolide induced an ROS-dependent increase in p53 abrogated telomerase activity. Costunolide decreased Nrf2 level; and ectopic Nrf2 expression decreased Costunolide-induced ROS generation. While TERT knock-down abrogated Nrf2 levels, overexpression of Nrf2 increased TERT expression. Inhibition of hTERT either by Costunolide, or by siRNA or dominant-negative hTERT (DN-hTERT) abrogated (i) expression of Glucose-6-phosphate dehydrogenase (G6PD) and Transketolase (TKT) - two major nodes in the pentose phosphate (PPP) pathway; and (ii) phosphorylation of glycogen synthase (GS). hTERT knock-down decreased TKT activity and increased glycogen accumulation. Interestingly, siRNA-mediated knock-down of TKT elevated glycogen accumulation. Coherent with the in vitro findings, Costunolide reduced tumor burden in heterotypic xenograft glioma mouse model. Costunolide-treated tumors exhibited diminished TKT activity, heightened glycogen accumulation, and increased senescence. Importantly, glioblastoma multiforme (GBM) patient tumors bearing TERT promoter mutations (C228T and C250T) known to be associated with increased telomerase activity; exhibited elevated Nrf2 and TKT expression and decreased glycogen accumulation. Taken together, our findings highlight the previously unknown (i) role of telomerase in the regulation of PPP and glycogen accumulation and (ii) the involvement of Nrf2-TERT loop in maintaining oxidative defense responses in glioma cells.

Evaluation of Skin Penetration of Diclofenac from a Novel Topical Non Aqueous Solution: A Comparative Bioavailability Study.

INTRODUCTION: Different topical formulations of diclofenac have varying skin penetration profile. Recent advances in science and technology has led to the development of many new formulations of drugs for topical drug delivery. One such technological development has led to the innovation of Dynapar QPS, a novel, non-aqueous, quick penetrating solution (QPS) of diclofenac diethylamine. AIM: This study was aimed to measure the total exposure from the drug penetrating the skin in healthy human subjects and comparing the relative systemic bioavailability of Dynapar QPS(®) with diclofenac emulgel. MATERIALS AND METHODS: A 200 mg of diclofenac from either Dynapar QPS(®) (5 ml) or emulgel (20 g) was applied on back of subject as per the randomisation schedule. Blood samples were collected up to 16 hours post drug application. Plasma concentration of diclofenac was measured by pre-validated HPLC method. Pharmacokinetic (PK) parameters like Cmax, Tmax, t1/2, AUC0-t, AUC0-∞, and Kel, of diclofenac were determined for both the formulations. RESULTS: Mean Cmax after administration of Dynapar QPS(®) and diclofenac emulgel were 175.93 and 40.04 ng/ml, respectively. Tmax of diclofenac was almost half with QPS compared to emulgel (5.24 hrs versus 9.53 hrs respectively). The mean AUC0-t and AUC0-∞ after administration of Dynapar QPS(®) was higher as compared to diclofenac emulgel (AUC0-t: 1224.19 versus 289.78 ng.h/ml, respectively; AUC0-∞: 1718.21 versus 513.83 ng.h/ml, respectively). None of the subject experienced any adverse event during the study. CONCLUSION: The results indicate an enhanced penetration and subsequent absorption of diclofenac from Dynapar QPS(®) as compared to diclofenac emulgel. Higher penetration is likely to translate into better pain relief in patients.

Chaetocin-induced ROS-mediated apoptosis involves ATM-YAP1 axis and JNK-dependent inhibition of glucose metabolism.

Oxidative stress serves as an important regulator of both apoptosis and metabolic reprogramming in tumor cells. Chaetocin, a histone methyltransferase inhibitor, is known to induce ROS generation. As elevating basal ROS level sensitizes glioma cells to apoptosis, the ability of Chaetocin in regulating apoptotic and metabolic adaptive responses in glioma was investigated. Chaetocin induced glioma cell apoptosis in a ROS-dependent manner. Increased intracellular ROS induced (i) Yes-associated protein 1 (YAP1) expression independent of the canonical Hippo pathway as well as (ii) ATM and JNK activation. Increased interaction of YAP1 with p73 and p300 induced apoptosis in an ATM-dependent manner. Chaetocin induced JNK modulated several metabolic parameters like glucose uptake, lactate production, ATP generation, and activity of glycolytic enzymes hexokinase and pyruvate kinase. However, JNK had no effect on ATM or YAP1 expression. Coherent with the in vitro findings, Chaetocin reduced tumor burden in heterotypic xenograft glioma mouse model. Chaetocin-treated tumors exhibited heightened ROS, pATM, YAP1 and pJNK levels. Our study highlights the coordinated control of glioma cell proliferation and metabolism by ROS through (i) ATM-YAP1-driven apoptotic pathway and (ii) JNK-regulated metabolic adaptation. The elucidation of these newfound connections and the roles played by ROS to simultaneously shift metabolic program and induce apoptosis could provide insights toward the development of new anti-glioma strategies.

Inhibition of Casein kinase-2 induces p53-dependent cell cycle arrest and sensitizes glioblastoma cells to tumor necrosis factor (TNFα)-induced apoptosis through SIRT1 inhibition.

Glioblastoma multiforme (GBM) are resistant to TNFα-induced apoptosis and blockade of TNFα-induced NF-κB activation sensitizes glioma cells to apoptosis. As Casein kinase-2 (CK2) induces aberrant NF-κB activation and as we observed elevated CK2 levels in GBM tumors, we investigated the potential of CK2 inhibitors (CK2-Is) - DRB and Apigenin in sensitizing glioma cells to TNFα-induced apoptosis. CK2-Is and CK2 small interfering RNA (siRNA) reduced glioma cell viability, inhibited TNFα-mediated NF-κB activation, and sensitized cell to TNFα-induced apoptosis. Importantly, CK2-Is activated p53 function in wild-type but not in p53 mutant cells. Activation of p53 function involved its increased transcriptional activation, DNA-binding ability, increased expression of p53 target genes associated with cell cycle progression and apoptosis. Moreover, CK2-Is decreased telomerase activity and increased senescence in a p53-dependent manner. Apoptotic gene profiling indicated that CK2-Is differentially affect p53 and TNFα targets in p53 wild-type and mutant glioma cells. CK2-I decreased MDM2-p53 association and p53 ubiquitination to enhance p53 levels. Interestingly, CK2-Is downregulated SIRT1 activity and over-expression of SIRT1 decreased p53 transcriptional activity and rescued cells from CK2-I-induced apoptosis. This ability of CK2-Is to sensitize glioma to TNFα-induced death via multiple mechanisms involving abrogation of NF-κB activation, reactivation of wild-type p53 function and SIRT1 inhibition warrants investigation.

Acridine orange stained blood wet mounts for fluorescent detection of malaria.

The age old Romanowsky stained thick blood smear examination for malarial parasites may fail to reveal the low parasitaemia. The commercial 'QBC' like acridine orange stained capillary tube preparation has a limitation of precise species identification and the detection of extra-erythrocytic parasites. Hence, the present study was aimed to improve malarial parasite detection by using acridine orange to stain large blood drops in the form of wet coverglass mounts. The acridine orange stained blood wet mounts over 2420 suspected malaria cases from Indore city were examined under fluorescent microscope and the results compared with the Leishman's stained thick blood smears in a blind study. The positivity of malarial parasites reported by the modified acridine orange staining was 248 against 109 by Leishman's stained thick blood smears. The modified acridine orange stained method is simple, instant and more efficient, requires less scanning time and skill, allows scanning of larger blood volume (75 ul) at lower magnification and the morphological details at higher magnification helps to make the precise species identification.