Curcumin is known for its anticancer and migrastatic activity in various cancers, including breast cancer. Newer curcumin derivatives are being explored to overcome limitations of curcumin like low ...bioavailability, stability, and side effects due to its higher dose. In this study, the synthesis of ST09, a novel curcumin derivative, and its antiproliferative, cytotoxic, and migrastatic properties have been explored both in vitro and in vivo.
After ST09 synthesis, anticancer activity was studied by performing standard cytotoxicity assays namely, lactate dehydrogenase (LDH) release assay, 3-(4, 5-dimethylthiazol-2-yl)-2-5-diphenyletrazolium bromide (MTT), and trypan blue exclusion assay. Annexin-FITC, cell cycle analysis using flow cytometry, and Western blotting were performed to elucidate cell death mechanisms. The effect on the inhibition of cell migration was studied by transwell migration assay. An EAC (Ehrlich Ascites carcinoma) induced mouse tumor model was used to study the effect of ST09 on tumor regression. Drug toxicity was measured using aspartate aminotransferase (AST), alanine aminotransferase (ALT), blood urea nitrogen (BUN), and flow-cytometry based lymphocyte count. Histological analysis was performed for assessment of any tissue injury post ST09 treatment.
ST09 shows an approximate 100-fold higher potency than curcumin, its parent compound, on breast tumor cell lines MCF-7 and MDA-MB231. ST09 arrests the cell cycle in a cell type-specific manner and induces an intrinsic apoptotic pathway both in vitro and in vivo. ST09 inhibits migration by downregulating matrix metalloprotease 1,2 (MMP1,2) and Vimentin. In vivo, ST09 administration led to decreased tumor volume in a mouse allograft model by boosting immunity with no significant drug toxicity.
ST09 exhibits antiproliferative and cytotoxic activity at nanomolar concentrations. It induces cell death by activation of the intrinsic pathway of apoptosis both in vitro and in vivo. It also inhibits migration and invasion. This study provides evidence that ST09 can potentially be developed as a novel antitumor drug candidate for highly metastatic and aggressive breast cancer.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
DNA Ligase IV is responsible for sealing of double-strand breaks (DSBs) during nonhomologous end-joining (NHEJ). Inhibiting Ligase IV could result in amassing of DSBs, thereby serving as a strategy ...toward treatment of cancer. Here, we identify a molecule, SCR7 that inhibits joining of DSBs in cell-free repair system. SCR7 blocks Ligase IV-mediated joining by interfering with its DNA binding but not that of T4 DNA Ligase or Ligase I. SCR7 inhibits NHEJ in a Ligase IV-dependent manner within cells, and activates the intrinsic apoptotic pathway. More importantly, SCR7 impedes tumor progression in mouse models and when coadministered with DSB-inducing therapeutic modalities enhances their sensitivity significantly. This inhibitor to target NHEJ offers a strategy toward the treatment of cancer and improvement of existing regimens.
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► SCR7, a Ligase IV inhibitor, blocks NHEJ in vitro and in vivo ► Inhibitor interferes with DNA binding domain association with double-strand breaks ► SCR7 impedes progression of tumors in mouse models, leading to enhanced lifespan ► Persistent breaks potentiate the effects of radio- and chemotherapy
Inhibition of Ligase IV, a key factor in nonhomologous end-joining, fosters apoptosis, impairs tumor growth, and enhances the efficacy of other chemotherapeutics in mouse models of cancer.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Advanced LIGO's raw detector output needs to be calibrated to compute dimensionless strain h(t). Calibrated strain data is produced in the time domain using both a low-latency, online procedure and a ...high-latency, offline procedure. The low-latency h(t) data stream is produced in two stages, the first of which is performed on the same computers that operate the detector's feedback control system. This stage, referred to as the front-end calibration, uses infinite impulse response (IIR) filtering and performs all operations at a 16 384 Hz digital sampling rate. Due to several limitations, this procedure currently introduces certain systematic errors in the calibrated strain data, motivating the second stage of the low-latency procedure, known as the low-latency gstlal calibration pipeline. The gstlal calibration pipeline uses finite impulse response (FIR) filtering to apply corrections to the output of the front-end calibration. It applies time-dependent correction factors to the sensing and actuation components of the calibrated strain to reduce systematic errors. The gstlal calibration pipeline is also used in high latency to recalibrate the data, which is necessary due mainly to online dropouts in the calibrated data and identified improvements to the calibration models or filters.
Resveratrol is one of the most widely studied bioactive plant polyphenols which possesses anticancer properties. Previously we have reported synthesis, characterization and identification of a novel ...resveratrol analog, SS28. In the present study, we show that SS28 induced cytotoxicity in several cancer cell lines ex vivo with an IC
value of 3-5 μM. Mechanistic evaluation of effect of SS28 in non-small cell lung cancer cell line (A549) and T-cell leukemic cell line (CEM) showed that it inhibited Tubulin polymerization during cell division to cause cell cycle arrest at G2/M phase of the cell cycle at 12-18 h time period. Immunofluorescence studies confirmed the mitotic arrest upon treatment with SS28. Besides, we show that SS28 binds to Tubulin with a dissociation constant of 0.414 ± 0.11 μM. Further, SS28 treatment resulted in loss of mitochondrial membrane potential, activation of Caspase 9 and Caspase 3, leading to PARP-1 cleavage and finally cell death via intrinsic pathway of apoptosis. Importantly, treatment with SS28 resulted in regression of tumor in mice. Hence, our study reveals the antiproliferative activity of SS28 by disrupting microtubule dynamics by binding to its cellular target Tubulin and its potential to be developed as an anticancer molecule.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
RB is a potato gene that provides resistance to a broad spectrum of genotypes of the late blight pathogen Phytophthora infestans. RB belongs to the CC-NB-LRR (coiled-coil, nucleotide-binding, ...leucine-rich repeat) class of resistance (R) genes, a major component of the plant immune system. The RB protein detects the presence of Class I and II IPI-O effectors from P. infestans to initiate a hypersensitive resistance response, but this activity is suppressed in the presence of the Class III effector IPI-O4. Using natural genetic variation of RB within potato wild relatives, we identified two amino acids in the CC domain that alter interactions needed for suppression of resistance by IPI-O4. We have found that separate modification of these amino acids in RB can diminish or expand the resistance capability of this protein against P. infestans in both Nicotiana benthamiana and potato. Our results demonstrate that increased knowledge of the molecular mechanisms that determine resistance activation and R protein suppression by effectors can be utilized to tailor-engineer genes with the potential to provide increased durability.
As sensitivities improve and more detectors are added to the global network of gravitational wave observatories, calibration accuracy and precision are becoming increasingly important. Photon ...calibrators, relying on power-modulated auxiliary laser beams reflecting from suspended interferometer optics, enable continuous calibration by generating displacement fiducials proportional to the modulated laser power. Developments in the propagation of laser power calibration via transfer standards to on-line power sensors monitoring the modulated laser power have enabled generation of length fiducials with improved accuracy. Estimated uncertainties are almost a factor of two smaller than the lowest values previously reported. This is partly due to improvements in methodology that have increased confidence in the results reported. Referencing the laser power calibration standards for each observatory to a single transfer standard enables reducing relative calibration errors between elements of the detector network. Efforts within the national metrology institute community to realize improved laser power sensor calibration accuracy are ongoing.
Prior observations have documented the process of cloud cleansing, through which cloudy, polluted air from a continent is slowly transformed into cloudy, clean air typical of a maritime environment. ...During that process, cloud albedo changes gradually, followed by a sudden reduction in cloud fraction and albedo as drizzle forms and convection changes from closed to open cellular. Experiments in a cloud chamber that generates a turbulent environment show a similar cloud cleansing process followed by rapid cloud collapse. Observations of (1) cloud droplet size distribution, (2) interstitial aerosol size distribution, (3) cloud droplet residual size distribution, and (4) water vapor supersaturation are all consistent with the hypothesis that turbulent fluctuations of supersaturation accelerate the cloud cleansing process and eventual cloud collapse. Decay of the interstitial aerosol concentration occurs slowly at first then more rapidly. The accelerated cleansing occurs when the cloud phase relaxation time exceeds the turbulence correlation time.
Plain Language Summary
Initially, polluted clouds can slowly transform into clean clouds when there is no significant source of aerosol particles. The rate at which this aerosol removal occurs, which can be thought of as cloud cleansing, undergoes a sudden acceleration when a cloud becomes sufficiently clean. Cloud chamber experiments show that random, turbulent fluctuations become large when a cloud becomes sufficiently clean, and these large fluctuations in temperature and the concentration of water vapor cause rapid activation of aerosol particles and rapid growth of cloud droplets. In the atmosphere these large droplets would be expected to aid in initiating the formation of precipitation by collisions and coalescence of droplets.
Key Points
Cloud cleansing of aerosols is simulated in a cloud chamber with steady state turbulence
Turbulent fluctuations in supersaturation become more pronounced as cloud is cleansed
Aerosol removal process is accelerated, leading to cloud collapse during the cleansing process
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Despite several treatment options for blood cancer, mortality remains high due to relapse and the disease's aggressive nature. Elevated levels of HSP90, a molecular chaperone essential for protein ...folding, are associated with poor prognosis in leukemia and lymphoma. HSP90 as a target for chemotherapy has been met with limited success due to toxicity and induction of heat shock. This study tested the activity of an HSP90 inhibitor, SP11, against leukemic cells, mouse lymphoma allograft, and xenograft models. SP11 induced cytotoxicity in vitro in leukemic cell lines and induced cell death via apoptosis, with minimal effect on normal cells. SP11 induced cell death by altering the status of HSP90 client proteins both in vitro and in vivo. SP11 reduced the tumor burden in allograft and xenograft mouse models without apparent toxicity. The half-life of SP11 in the plasma was approximately 2 h. SP11 binding was observed at both the N-terminal and C-terminal domains of HSP90. C-terminal binding was more potent than N-terminal binding of HSP90 in silico and in vitro using isothermal calorimetry. SP11 bioavailability and minimal toxicity in vivo make it a potential candidate to be developed as a novel anticancer agent.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Calibration of the second-generation LIGO interferometric gravitational-wave detectors employs a method that uses injected periodic modulations to track and compensate for slow temporal variations in ...the differential length response of the instruments. These detectors utilize feedback control loops to maintain resonance conditions by suppressing differential arm length variations. We describe how the sensing and actuation functions of these servo loops are parameterized and how the slow variations in these parameters are quantified using the injected modulations. We report the results of applying this method to the LIGO detectors and show that it significantly reduces systematic errors in their calibrated outputs.
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