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In this study, variations in physicochemical parameters and heavy metal contamination in water–sediments of a natural stream in the Durgapur industrial zone have been investigated. pH, COD, Cl−, CN− and heavy metals, viz. Pb, Hg and Fe concentrations in channel water, are higher than Indian standards. Metal concentrations in sediments are many folds higher than background value, where Pb, Cd, Hg and Cr contents exceed the sediment quality guidelines. Contamination factor (Cf) value of channel water follows the order of Hg > Pb > Fe > Cr > Cd > Cu > Ni, whereas enrichment factor and geo-accumulation index (Igeo) values in channel sediments are in the order of Hg > Cr > Ni > Pb > Cd > Fe > Cu. The assessment of contamination index (Cd), modified contamination index (mCd) and pollution load index indicates that channel water and sediment samples in the study area are strongly contaminated by heavy metals. Sediment samples based on PELQ and ERMQ are highly toxic, with high degree of potential ecological risk at all the monitored stations. Multivariate analysis infers that heavy metals in channel water and sediments are majorly sourced from industrial discharge.

Elevated extracellular potassium chloride is widely used to achieve membrane depolarization of cultured neurons. This technique has illuminated mechanisms of calcium influx through L-type voltage sensitive calcium channels, activity-regulated signaling, downstream transcriptional events, and many other intracellular responses to depolarization. However, there is enormous variability in these treatments, including durations from seconds to days and concentrations from 3mM to 150 mM KCl. Differential effects of these variable protocols on neuronal activity and transcriptional programs are underexplored. Furthermore, potassium chloride treatments in vitro are criticized for being poor representatives of in vivo phenomena and are questioned for their effects on cell viability. In this review, we discuss the intracellular consequences of elevated extracellular potassium chloride treatment in vitro, the variability of such treatments in the literature, the strengths and limitations of this tool, and relevance of these studies to brain functions and dysfunctions.

The present study involves bacterial cellulose (BC) production using freshly prepared apple juice medium (AJM) and the bacterial strain Gluconobacter xylinum CCM 3611T. The AJM was modified with ammonium sulfate, dipotassium phosphate, sucrose, acetic acid, with and without ethanol. BC sheets (in the dry state) were analyzed on the basis of morphological, rheological and structural properties, thermal stability, water holding capacity (WHC) and water absorption capacity (WAC). Comparative X-ray diffractograms of BC using cobalt radiation is observed for the first time. The WAC analysis revealed that lyophilized BC samples had the higher WAC than the oven air-dried samples. There is an evidential structural difference observed in BC prepared from different AJM. Moreover, the AJM modified with only ethanol, exhibited quite a significant yield of BC. BC produced from the medium without ethanol had the highest thermal stability, viscoelasticity, and WHC.

The low frequency of p53 alterations e.g., mutations/deletions (∼10%) in multiple myeloma (MM) makes this tumor type an ideal candidate for p53-targeted therapies. RITA is a small molecule which can induce apoptosis in tumor cells by activating the p53 pathway. We previously showed that RITA strongly activates p53 while selectively inhibiting growth of MM cells without inducing genotoxicity, indicating its potential as a drug lead for p53-targeted therapy in MM. However, the molecular mechanisms underlying the pro-apoptotic effect of RITA are largely undefined. Gene expression analysis by microarray identified a significant number of differentially expressed genes associated with stress response including c-Jun N-terminal kinase (JNK) signaling pathway. By Western blot analysis we further confirmed that RITA induced activation of p53 in conjunction with up-regulation of phosphorylated ASK-1, MKK-4 and c-Jun. These results suggest that RITA induced the activation of JNK signaling. Chromatin immunoprecipitation (ChIP) analysis showed that activated c-Jun binds to the activator protein-1 (AP-1) binding site of the p53 promoter region. Disruption of the JNK signal pathway by small interfering RNA (siRNA) against JNK or JNK specific inhibitor, SP-600125 inhibited the activation of p53 and attenuated apoptosis induced by RITA in myeloma cells carrying wild type p53. On the other hand, p53 transcriptional inhibitor, PFT-α or p53 siRNA not only inhibited the activation of p53 transcriptional targets but also blocked the activation of c-Jun suggesting the presence of a positive feedback loop between p53 and JNK. In addition, RITA in combination with dexamethasone, known as a JNK activator, displays synergistic cytotoxic responses in MM cell lines and patient samples. Our study unveils a previously undescribed mechanism of RITA-induced p53-mediated apoptosis through JNK signaling pathway and provides the rationale for combination of p53 activating drugs with JNK activators in the treatment of MM.

The present study deals with the characterization of effluent released from sponge iron industries and distribution of heavy metals in soil and macrophytes near to effluent discharge channel. Apart from this, accumulation of heavy metals in nearby soil and vegetation system irrigated with effluent-contaminated water is also the subject of this study. Physico-chemical analysis of effluent reveals that the concentration of total suspended solids (TSS), total hardness (TH), iron (Fe2+), and oil and grease are greater than the IS (1981) norms for discharge of water into inland water body. The soil along the sides of the effluent channel also shows higher concentration of heavy metals than the background soil. The enrichment of the heavy metals are in the order of Chromium (Cr) > Iron (Fe) > Manganese (Mn) > Zinc (Zn) > Copper (Cu) > Cadmium (Cd). Macrophytes growing along the sides of the effluent channel also show significant accumulation of heavy metals almost in the same order as accumulated in soil. Higher uptake of heavy metals by these varieties reveals that these species can be used for future phytoremediation. The effluent as well as contaminated water is extensively used for irrigation for growing vegetables like tomato (Lycopersicon esculatum) in the surrounding areas. Heavy metal accumulation in this agricultural soil are in the sequence of Cr > Fe > Mn > Zn > Cu > Cd. More or less similar type of accumulation pattern are also found in tomato plants except Fe and Zn exceeding Cr and Mn. Transfer Factor of heavy metals from soil to tomato plants (TFS) shows average value of <1, suggesting less uptake of heavy metals from soil. Among the plant parts studied, fruit shows least accumulation. Although tomato plants show some phenotypic changes, the survival of tomato plants as well as least accumulation of metals in fruit reveals their tolerance to heavy metals. Therefore it may be suggested that this plant can be grown successfully in the heavy metal contaminated soil. Further research work on in situ toxicity test will be necessary in order to identify the most resistive variety on this particular type of contaminated site. (PUBLICATION ABSTRACT)

p53 is a powerful tumor suppressor and is an attractive cancer therapeutic target. A breakthrough in cancer research came from the discovery of the drugs which are capable of reactivating p53 function. Most anti-cancer agents, from traditional chemo- and radiation therapies to more recently developed non-peptide small molecules exert their effects by enhancing the anti-proliferative activities of p53. Small molecules such as nutlin, RITA, and PRIMA-1 that can activate p53 have shown their anti-tumor effects in different types of hematological malignancies. Importantly, nutlin and PRIMA-1 have successfully reached the stage of phase I/II clinical trials in at least one type of hematological cancer. Thus, the pharmacological activation of p53 by these small molecules has a major clinical impact on prognostic use and targeted drug design. In the current review, we present the recent achievements in p53 research using small molecules in hematological malignancies. Anticancer activity of different classes of compounds targeting the p53 signaling pathway and their mechanism of action are discussed. In addition, we discuss how p53 tumor suppressor protein holds promise as a drug target for recent and future novel therapies in these diseases.

Multiple myeloma (MM) is incurable in virtually all patients due to the presence of innate and emergent drug-resistance. To identify potential drug resistance mechanisms in MM we used iTRAQ (isobaric tags for relative and absolute quantitation) mass spectrometry to compare protein expression profiles of drug-resistant (RPMI 8226-R5) and sensitive (RPMI 8226-S) isogenic cell lines. We identified selective overexpression of myristoylated alanine-rich C-kinase substrate (MARCKS) in drug-resistant R5 cells. MARCKS overexpression was also observed in several drug-resistant human myeloma cell lines (HMCLs) and in drug-resistant primary MM samples. Functionally, inhibition of MARCKS phosphorylation by enzastaurin or knockdown of the gene by RNAi significantly enhanced the sensitivity of resistant HMCLs and primary MM samples to bortezomib and to other anti-myeloma drugs, providing evidence that MARCKS can modulate drug response. Mechanistically, pMARCKS (phosphorylated form of MARCKS) was found to function as an E2F-1 cofactor to regulate SKP2 transcription. pMARCKS promoted cell-cycle progression by facilitating SKP2 expression, suppressing p27 Kip1 and potentially counteracting drug-induced cell-cycle arrest by promoting Cyclin E/CDK2 activity. Importantly, MARCKS knockdown in combination with bortezomib treatment overcame bortezomib resistance, significantly inhibited tumor growth and prolonged host survival in a MM xenograft model. These data provide a rationale for therapeutic targeting of pMARCKS to improve the outcome of patients with refractory/relapsed MM.

Immediate early genes are rapidly transcribed in response to neuronal activity, but the underlying mechanism is unclear. The authors show that this rapid transcription is mediated by a stalled RNA polymerase II, poised just downstream of the transcription start site. RNAi-depletion of negative elongation factor compromises the rapid transcription. Transcription of immediate early genes (IEGs) in neurons is highly sensitive to neuronal activity, but the mechanism underlying these early transcription events is largely unknown. We found that several IEGs, such as Arc (also known as Arg3.1 ), are poised for near-instantaneous transcription by the stalling of RNA polymerase II (Pol II) just downstream of the transcription start site in rat neurons. Depletion through RNA interference of negative elongation factor, a mediator of Pol II stalling, reduced the Pol II occupancy of the Arc promoter and compromised the rapid induction of Arc and other IEGs. In contrast, reduction of Pol II stalling did not prevent transcription of IEGs that were expressed later and largely lacked promoter-proximal Pol II stalling. Together, our data strongly indicate that the rapid induction of neuronal IEGs requires poised Pol II and suggest a role for this mechanism in a wide variety of transcription-dependent processes, including learning and memory.

Background Tofacitinib—an oral JAK inhibitor—has been recently approved by US FDA to treat moderate to severe RA. The delivery of tofacitinib to specific inflammation site at joint via topical route using nanoformulations helps in managing the potential adverse effects. The objective is to develop and validate a simple, specific, and sensitive stability-indicating HPLC method for quantification of tofacitinib in topical nanoformulations and different matrices (adhesive tape, and skin layers, i.e., stratum corneum, viable epidermis, and dermis). The major objective was to avoid use of instruments like LC–MS/MS and to ensure a widespread application of the method. Result A 3 2 factorial ‘design of experiments’ was applied to optimize process variables, to understand the effect of variables on peak properties. The calibration curve showed regression coefficient ( R 2 ) 0.9999 and linearity in the concentration range of 50 to 15,000 ng/mL, which is suitable for the analysis of conventional dosage forms and nanoformulations. Method validation was performed as per ICH guideline Q2 (R1). The accuracy by recovery studies ranged between 98.09 and 100.82%. The % relative standard deviations in intraday and interday precisions were in the range of 1.16–1.72 and 1.22–1.80%, respectively. Forced degradation studies indicated the specificity of method and showed stability-indicating potential for tofacitinib peak. Conclusion The validated method provides a quantification method of tofacitinib in the presence of formulation excipients, dissolution media, and skin tissues in detail. In addition, the method was successfully utilized for determination of various dermatokinetics profile of tofacitinib.

Background: Preliminary reports and subsequent immediate management decisions of radiological scans are often performed by emergency physicians and on-call radiology residents. Many academic hospitals have resident-only coverage for after-hour shifts. Generally, these preliminary reports are eventually reviewed by a staff radiologist, during which discrepancies may be identified. Depending on the severity of the discrepancy and the time taken to notify the treating physician, there is potential for significant impact on the patient's care. Aim Statement: In an attempt to identify and minimize errors in radiological readings, and to improve the communication of discrepancies, our project aims to retrospectively audit all radiological discrepancies that have occurred at The Ottawa Hospital's emergency departments from April 2018 to May 2019. Measures & Designs: A systematic review of all cases with noted radiological discrepancies was obtained from the Picture Archive and Communication System software and EPIC platform. Analysis of these cases will allow us to define when errors occur, what is the type and severity of the error, how long it took to relay the discrepancy to a treating physician, and what was the subsequent management impact. Evaluation/Results: We discovered 712 cases with radiological reading discrepancies, 168 major, 527 minor, and 17 incidentals. Interestingly, a significant portion of major (severely affecting care/life-threatning) discrepancies were reported from radiology residents, especially on CT images, although emergency physicians had the most discrepancies (mostly minor). Radiology residents were seen to have more discrepant reports during after-hour services while emergency physicians did not show any specific pattern of discrepant reporting. The average time to report a major discrepancy to a treating physician is 8.8 hours, where the maximum time taken was 104 hours and the minimum was 0.2 hours. 56% of reports with major discrepancies made no mention of who was notified. Discussion/Impact: By identifying weak points in radiological reporting, our results will allow us to provide suggestions at an administration and teaching level to minimize discrepancies. It is critical to create a workflow where mistakes are mitigated, and communication is efficient and standardized to prevent patient harm from delayed or incorrect diagnosis.