ORCID Profile
0000-0001-7108-5345
Current Organisation
University of South Australia
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Publisher: Wiley
Date: 08-05-2018
DOI: 10.1111/BPH.13974
Publisher: Copernicus GmbH
Date: 23-09-2020
Abstract: Abstract. The Northern Antarctic Peninsula (NAP) is a highly dynamic transitional zone between the subpolar-polar and oceanic-coastal environments, and it is located in an area affected by intense climate change, including intensification and spatial shifts of the westerlies as well as atmospheric and oceanic warming. In the NAP area, the water masses originate mainly from the Bellingshausen and Weddell Seas, which create a marked regional dichotomic thermohaline characteristic. Although the NAP area has relatively easy access when compared to other Southern Ocean environments, our understanding of the water masses distribution and the dynamical processes affecting the variability of the region is still limited. That limitation is closely linked to the sparse data coverage, as commonly is the case in most of the Southern Ocean environments. This work provides a novel three-dimensional high-resolution hydrographic gridded data set for the NAP, namely the GOAL gridded product. Hydrographic measurements from 2003–2019 have been optimally interpolated to produce maps of conservative temperature, absolute salinity, neutral density and dissolved oxygen at ~10 km spatial resolution and 114 depth levels. The water masses and oceanographic features in this regional gridded product are more accurate than other climatologies and state estimate products currently available. The data sets are available in netCDF format at www.goal.furg.br roducao-cientifica/supplements/203-goal-gridded-nap and at 0.5281/zenodo.3989548 (Dotto et al., 2020). The novel GOAL gridded product and comprehensive data sets presented here are a valuable tool to be used in studies addressing climatological changes in the unique NAP region since they provide accurate initial conditions for ocean models and improve the early 21st-century ocean mean-summer-state representation for that area.
Publisher: American Association for Cancer Research (AACR)
Date: 14-07-2018
DOI: 10.1158/1538-7445.AM2017-2353
Abstract: Cyclin D dependent kinases CDK4 & CDK6 are crucial regulators of the G1 to S phase transition of the cell cycle. The facts that myriad cancer types show aberrance in INK4-CDK4/6-cyclin D-Rb-E2F pathway, & the rapidly emerging positive clinical data of pharmacological inhibitors have validated CDK4/6 as anticancer drug targets. As the first commercialized CDK inhibitor, palbociclib in combination with letrozole or fulvestrant has received regulatory approval for the treatment of breast cancer. This represents an important scientific advance in the field. However, the limited structural ersity & undesired side effects due to broader kinase interactions of existing inhibitors mean that the hunt for new & highly selective CDK4/6 inhibitor drug candidates continues. Using our advanced medicinal chemistry, targeted biochemical & cell-based assays, & animal pharmacology, we synthesized & evaluated a novel series of inhibitors. Many compounds were highly potent & selective against CDK4/6, & exhibited low nanomolar potency against a range of human cancer cell lines. Notably, inhibition of CDK4D1 by compound CDKI-15 (Ki = 4 nM) was over 3 orders of magnitude greater than CDK1B, CDK2A, CDK7H & CDK9T1. Interrogation of a panel of 369 protein kinases revealed CDKI-15 to be highly selective for CDK4/6 with only 3 other kinases inhibited potently. CDKI-15 reduced the level of Rb phosphorylation & induced G1 cell cycle arrest, confirming cellular inhibition of CDK4/6 in cancer cells. Moreover, CDKI-15 possesses superior pharmacokinetic profile with oral bioavailability of 100% in mice. Treatment of nude BALB/c mice bearing human MV4-11 acute myeloid leukemia cells with CDKI-15 at daily dose of 100 mg/kg by oral administration resulted in a robust inhibition of tumor growth compared to vehicle treated animals (T/C = 30%, p & 0.00001). Strikingly, CDKI-15 caused a complete & sustained tumor regression in one-third of the animals. No detectable toxicity was observed in the animals during & post treatment. Taken together, our data provide a rationale for CDKI-15 to be developed towards clinic for cancer therapy. Citation Format: Solomon Tadesse, Laychiluh Bantie, Khamis Tomusange, Saiful Islam, Muhammed H. Rahaman, Benjamin Noll, Frankie Lam, Mingfeng Yu, Shudong Wang. CDKI-15, a novel and highly selective CDK4/6 inhibitor: discovery, in vitro and in vivo anticancer efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017 2017 Apr 1-5 Washington, DC. Philadelphia (PA): AACR Cancer Res 2017 (13 Suppl):Abstract nr 2353. doi:10.1158/1538-7445.AM2017-2353
Publisher: Copernicus GmbH
Date: 15-05-2023
DOI: 10.5194/EGUSPHERE-EGU23-8902
Abstract: Warm ocean waters drive rapid ice-shelf melting in the Amundsen Sea. The ocean heat transport toward the ice shelves is associated with the Amundsen Undercurrent, a near-bottom current that flows eastward along the shelf break and transports warm waters onto the continental shelf via troughs. Here we use a regional ice-ocean model to show that, on decadal time scales, the undercurrent's variability is baroclinic (depth-dependent). Decadal ocean surface cooling in the tropical Pacific results in cyclonic wind anomalies over the Amundsen Sea. These wind anomalies drive a westward perturbation of the shelf-break surface& flow and an eastward anomaly (strengthening) of the undercurrent, leading to increased ice-shelf melting. This contrasts with shorter time scales, for which surface current and undercurrent covary, a barotropic (depth-independent) behavior previously assumed to apply at all time scales. This suggests that interior ocean processes mediate the decadal ice-shelf response in the Amundsen Sea to climate forcing.
Publisher: MDPI AG
Date: 25-03-2023
DOI: 10.3390/MOLECULES28072951
Abstract: Cyclin-dependent kinase 2 (CDK2) has been garnering considerable interest as a target to develop new cancer treatments and to ameliorate resistance to CDK4/6 inhibitors. However, a selective CDK2 inhibitor has yet to be clinically approved. With the desire to discover novel, potent, and selective CDK2 inhibitors, the phenylsulfonamide moiety of our previous lead compound 1 was bioisosterically replaced with pyrazole derivatives, affording a novel series of N,4-di(1H-pyrazol-4-yl)pyrimidin-2-amines that exhibited potent CDK2 inhibitory activity. Among them, 15 was the most potent CDK2 inhibitor (Ki = 0.005 µM) with a degree of selectivity over other CDKs tested. Meanwhile, this compound displayed sub-micromolar antiproliferative activity against a panel of 13 cancer cell lines (GI50 = 0.127–0.560 μM). Mechanistic studies in ovarian cancer cells revealed that 15 reduced the phosphorylation of retinoblastoma at Thr821, arrested cells at the S and G2/M phases, and induced apoptosis. These results accentuate the potential of the N,4-di(1H-pyrazol-4-yl)pyrimidin-2-amine scaffold to be developed into potent and selective CDK2 inhibitors for the treatment of cancer.
Publisher: Elsevier BV
Date: 05-2023
Publisher: Elsevier BV
Date: 07-2015
Publisher: American Chemical Society (ACS)
Date: 20-03-2019
Publisher: American Geophysical Union (AGU)
Date: 08-2020
DOI: 10.1029/2020JC016113
Publisher: Copernicus GmbH
Date: 23-06-2014
Abstract: Abstract. We assessed and evaluated the performance of five ocean reanalysis products in reproducing essential hydrographic properties and their associated temporal variability for the Weddell Sea, Antarctica. The products used in this assessment were ECMWF ORAS4 (European Centre for Medium-Range Weather Forecasts Ocean Reanalysis System 4), CFSR (Climate Forecast System Reanalysis), MyOcean UR025.4 (University of Reading), ECCO2 (Estimating the Circulation and Climate of the Ocean, Phase II) and SODA (Simple Ocean Data Assimilation). The present study focuses on the Weddell Sea deep layer, which is composed of the following three main water masses: Warm Deep Water (WDW), Weddell Sea Deep Water (WSDW) and Weddell Sea Bottom Water (WSBW). The MyOcean UR025.4 product provided the most accurate representation of the structure and thermohaline properties of the Weddell Sea water masses when compared with observations. All the ocean reanalysis products analyzed exhibited limited capabilities in representing the surface water masses in the Weddell Sea. The CFSR and ECCO2 products were not able to represent deep water masses with a neutral density ≥ 28.40 kg m−3, which was considered the WSBW's upper limit throughout the simulation period. The expected WDW warming was only reproduced by the SODA product, whereas the ECCO2 product was able to represent the trends in the WSDW's hydrographic properties. All the assessed ocean reanalyses were able to represent the decrease in the WSBW's density, except the SODA product in the inner Weddell Sea. Improvements in parameterization may have as much impact on the reanalyses assessed as improvements in horizontal resolution primarily because the Southern Ocean lacks in situ data, and the data that are currently available are summer-biased. The choice of the reanalysis product should be made carefully, taking into account the performance, the parameters of interest, and the type of physical processes to be evaluated.
Publisher: Bentham Science Publishers Ltd.
Date: 26-08-2019
DOI: 10.2174/1573406415666181219111511
Abstract: Aberrant expression of eukaryotic translation initiation factor 4E (eIF4E) is common in many types of cancer including acute myeloid leukaemia (AML). Phosphorylation of eIF4E by MAPK-interacting kinases (Mnks) is essential for the eIF4E-mediated oncogenic activity. As such, the pharmacological inhibition of Mnks can be an effective strategy for the treatment of cancer. A series of N-phenyl-4-(1H-pyrrol-3-yl)pyrimidin-2-amine derivatives was designed and synthesised. The Mnk inhibitory activity of these derivatives as well as their anti-proliferative activity against MV4-11 AML cells was determined. These compounds were identified as potent Mnk2 inhibitors. Most of them demonstrated potent anti-proliferative activity against MV4-11 AML cells. The cellular mechanistic studies of the representative inhibitors revealed that they reduced the level of phosphorylated eIF4E and induced apoptosis by down-regulating the anti-apoptotic protein myeloid cell leukaemia 1 (Mcl-1) and by cleaving poly(ADP-ribose)polymerase (PARP). The lead compound 7k possessed desirable pharmacokinetic properties and oral bioavailability. This work proposes that exploration of the structural ersity in the context of Nphenyl- 4-(1H-pyrrol-3-yl)pyrimidin-2-amine would offer potent and selective Mnk inhibitors.
Publisher: Copernicus GmbH
Date: 26-02-2021
Abstract: Abstract. The northern Antarctic Peninsula (NAP) is a highly dynamic transitional zone between the subpolar-polar and oceanic-coastal environments, and it is located in an area affected by intense climate change, including intensification and spatial shifts of the westerlies as well as atmospheric and oceanic warming. In the NAP area, the water masses originate mainly from the Bellingshausen and Weddell seas, which create a marked regional dichotomy thermohaline characteristic. Although the NAP area has relatively easy access when compared to other Southern Ocean environments, our understanding of the water masses' distribution and the dynamical processes affecting the variability of the region is still limited. That limitation is closely linked to the sparse data coverage, as is commonly the case in most Southern Ocean environments. This work provides a novel seasonal three-dimensional high-resolution hydrographic gridded data set for the NAP (version 1), namely the NAPv1.0. Hydrographic measurements from 1990 to 2019 comprising data collected by conductivity, temperature, depth (CTD) casts sensors from the Marine Mammals Exploring the Oceans Pole to Pole (MEOP) consortium and Argo floats have been optimally interpolated to produce maps of in situ temperature, practical salinity, and dissolved oxygen at ∼ 10 km spatial resolution and 90 depth levels. The water masses and oceanographic features in this regional gridded product are more accurate than other climatologies and state estimate products currently available. The data sets are available in netCDF format at 0.5281/zenodo.4420006 (Dotto et al., 2021). The novel and comprehensive data sets presented here for the NAPv1.0 product are a valuable tool to be used in studies addressing climatological changes in the unique NAP region since they provide accurate initial conditions for ocean models and improve the end of the 20th- and early 21st-century ocean mean-state representation for that area.
Publisher: Hindawi Limited
Date: 2015
DOI: 10.1155/2015/138073
Abstract: Background . In Ethiopia, up to 80% of the population use traditional medicine for primary health care. Studies on the current knowledge and practices of communities in the era of modern health care expansion are lacking. Therefore, this study is aimed at assessing the knowledge, attitude, and practice of traditional medicine among communities in Merawi town. Methods . A descriptive cross-sectional study was carried out among 403 residents of Merawi town. A systematic random s ling was used to select households. Data was collected through house to house interview. Results . 392 out of 403 questionnaires were analysed. Among the participants, 220 (56.1%) were female. The mean (±s.d.) age of the participants was 32.5 (±12.4) years. Nearly two-thirds, 241 (61.5%), of study participants have good knowledge about traditional medicines. Three-quarters of participants prefer modern medicine to traditional drugs. 70.9% of participants had the experience of personal use of traditional therapies. Conclusions . The population in Merawi has good knowledge with high acceptability and use of traditional medicine. The main reasons for high acceptability and practice were cultural acceptability, lesser cost, and good outcome of traditional medicine.
Publisher: Elsevier BV
Date: 03-2021
Publisher: Future Science Ltd
Date: 09-2017
Abstract: Aim: Inhibitors of CDK4/6 have emerged as a powerful class of therapeutics for treatment of several malignancies. We herein describe the identification of a new series of molecules that demonstrated excellent selectivity for CDK4/6 over CDKs1, 7 and 9. Results: Medicinal chemistry optimization led to the discovery of 58 and 69 that inhibited CDK4 and CDK4/6, respectively, with high potency and selectivity, and 58 and 69 exhibited potent antiproliferative activities in a panel of human cancer cell lines including leukemia, and cancers of the breast, colon, ovary, pancreas and prostate. Conclusion: Compounds 58 and 69 caused remarkable growth inhibition of melanoma cells, particularly the cells harboring multiple BRAF and NRAS mutations, via a CDK4/6-targeted mechanism of action. [Formula: see text]
Publisher: Public Library of Science (PLoS)
Date: 17-09-2015
Publisher: Copernicus GmbH
Date: 14-02-2014
Abstract: Abstract. We assessed and evaluated the performance of five ocean reanalysis in reproducing essential hydrographic properties and their associated temporal variability for the Weddell Sea, Antarctica. The products used in this assessment were ECMWF ORAS4, CFSR, MyOcean UR025.4, ECCO2 and SODA. The present study focuses on the Weddell Sea deep layer, which is composed of the following three main water masses: Warm Deep Water (WDW), Weddell Sea Deep Water (WSDW) and Weddell Sea Bottom Water (WSBW). Moreover, all the ocean reanalysis products analyzed showed limited capabilities in representing the surface water masses in the Weddell Sea. The MyOcean UR025.4 product provided the most accurate representation of the structure of the Weddell Sea water masses when compared to observations. The CFSR and ECCO2 products were not able to represent the WSBW throughout the simulation period. The expected WDW warming was only reproduced by the SODA product, while the ECCO2 product was able to represent the WSDW's hydrographic properties trends. All of these ocean reanalysis systems were able to represent the decrease in the WSBW's density. Our results also showed that a simple increase in horizontal resolution does not necessarily imply better representation of the deep layers. Rather, it is needed to observe the physics involved in each model and their parameterizations because the Southern Ocean suffers from the lack of in situ data, and it is biased by summer observations. The choice of the reanalysis product should be made carefully, taking into account the performance, the parameters of interest, and the type of physical processes to be evaluated.
Publisher: Springer Science and Business Media LLC
Date: 03-2014
Publisher: Elsevier BV
Date: 12-2020
Publisher: Wiley
Date: 02-2023
DOI: 10.1111/GCB.16602
Abstract: The western Antarctic Peninsula (WAP) is a climatically sensitive region where foundational changes at the basis of the food web have been recorded cryptophytes are gradually outgrowing diatoms together with a decreased size spectrum of the phytoplankton community. Based on a 11‐year (2008–2018) in‐situ dataset, we demonstrate a strong coupling between biomass accumulation of cryptophytes, summer upper ocean stability, and the mixed layer depth. Our results shed light on the environmental conditions favoring the cryptophyte success in coastal regions of the WAP, especially during situations of shallower mixed layers associated with lower diatom biomass, which evidences a clear competition or niche segregation between diatoms and cryptophytes. We also unravel the cryptophyte photo‐physiological niche by exploring its capacity to thrive under high light stress normally found in confined stratified upper layers. Such conditions are becoming more frequent in the Antarctic coastal waters and will likely have significant future implications at various levels of the marine food web. The competitive advantage of cryptophytes in environments with significant light level fluctuations was supported by laboratory experiments that revealed a high flexibility of cryptophytes to grow in different light conditions driven by a fast photo‐regulating response. All tested physiological parameters support the hypothesis that cryptophytes are highly flexible regarding their growing light conditions and extremely efficient in rapidly photo‐regulating changes to environmental light levels. This plasticity would give them a competitive advantage in exploiting an ecological niche where light levels fluctuate quickly. These findings provide new insights on niche separation between diatoms and cryptophytes, which is vital for a thorough understanding of the WAP marine ecosystem.
Publisher: Wiley
Date: 27-11-2023
Abstract: Cyclin‐dependent kinases (CDKs) 7 and 9 are deregulated in various types of human cancer and are thus viewed as therapeutic targets. Accordingly, small‐molecule inhibitors of both CDKs are highly sought‐after. Capitalising on our previous discovery of CDKI‐73, a potent CDK9 inhibitor, medicinal chemistry optimisation was pursued. A number of N ‐pyridinylpyrimidin‐2‐amines were rationally designed, chemically synthesised and biologically assessed. Among them, N ‐(6‐(4‐cyclopentylpiperazin‐1‐yl)pyridin‐3‐yl)‐4‐(imidazo[1,2‐ a ]pyrimidin‐3‐yl)pyrimidin‐2‐amine was found to be one of the most potent inhibitors of CDKs 7 and 9 as well as the most effective anti‐proliferative agent towards multiple human cancer cell lines. The cellular mode of action of this compound was investigated in MV4‐11 acute myeloid leukaemia cells, revealing that the compound d ened the kinase activity of cellular CDKs 7 and 9, arrested the cell cycle at sub‐G1 phase and induced apoptosis.
Publisher: American Association for Cancer Research (AACR)
Date: 07-2018
Publisher: MDPI AG
Date: 22-02-2022
Abstract: Mutations in FMS-like tyrosine kinase 3 (FLT3) occur in approximately one-third of AML patients and are associated with a particularly poor prognosis. The most common mutation, FLT3-ITD, is a self-activating internal tandem duplication (ITD) in the FLT3 juxtamembrane domain. Many FLT3 inhibitors have shown encouraging results in clinical trials, but the rapid emergence of resistance has severely limited sustainable efficacy. Co-targeting of CDK9 and FLT3 is a promising two-pronged strategy to overcome resistance as the former plays a role in the transcription of cancer cell-survival genes. Most prominently, MCL-1 is known to be associated with AML tumorigenesis and drug resistance and can be down-regulated by CDK9 inhibition. We have developed CDDD11-8 as a potent CDK9 inhibitor co-targeting FLT3-ITD with Ki values of 8 and 13 nM, respectively. The kinome selectivity has been confirmed when the compound was tested in a panel of 369 human kinases. CDDD11-8 displayed antiproliferative activity against leukemia cell lines, and particularly potent effects were observed against MV4-11 and MOLM-13 cells, which are known to harbor the FLT3-ITD mutation and mixed lineage leukemia (MLL) fusion proteins. The mode of action was consistent with inhibition of CDK9 and FLT3-ITD. Most importantly, CDDD11-8 caused a robust tumor growth inhibition by oral administration in animal xenografts. At 125 mg/kg, CDDD11-8 induced tumor regression, and this was translated to an improved survival of animals. The study demonstrates the potential of CDDD11-8 towards the future development of a novel AML treatment.
Publisher: Bioscientifica
Date: 12-2016
DOI: 10.1530/ERC-16-0299
Abstract: Cyclin-dependent kinase 9 (CDK9) is a key transcriptional regulator and a lucrative target for cancer treatment. Targeting CDK9 can effectively confine the hyperactivity of androgen receptor and the constitutive expression of anti-apoptotic proteins both being main causes of prostate cancer (PCa) development and progression. In castrate-resistant PCa, traditional therapies that only target androgen receptor (AR) have become obsolete due to reprograming in AR activity to make the cells independent of androgen. CDK9 inhibitors may provide a new and better therapeutic opportunity over traditional treatment options by targeting both androgen receptor activity and anti-apoptotic proteins, improving the chances of positive outcomes, especially in patients with the advanced disease. This review focuses on biological functions of CDK9, its involvement with AR and the potential for therapeutic opportunities in PCa treatment.
Publisher: American Association for Cancer Research (AACR)
Date: 07-2018
Publisher: Elsevier BV
Date: 02-2023
Publisher: American Chemical Society (ACS)
Date: 16-02-2017
DOI: 10.1021/ACS.JMEDCHEM.6B01670
Abstract: Cyclin D dependent kinases (CDK4 and CDK6) regulate entry into S phase of the cell cycle and are validated targets for anticancer drug discovery. Herein we detail the discovery of a novel series of 4-thiazol-N-(pyridin-2-yl)pyrimidin-2-amine derivatives as highly potent and selective inhibitors of CDK4 and CDK6. Medicinal chemistry optimization resulted in 83, an orally bioavailable inhibitor molecule with remarkable selectivity. Repeated oral administration of 83 caused marked inhibition of tumor growth in MV4-11 acute myeloid leukemia mouse xenografts without having a negative effect on body weight and showing any sign of clinical toxicity. The data merit 83 as a clinical development candidate.
Publisher: American Geophysical Union (AGU)
Date: 14-12-2022
DOI: 10.1029/2022GL100646
Abstract: Warm ocean waters drive rapid ice‐shelf melting in the Amundsen Sea. The ocean heat transport toward the ice shelves is associated with the Amundsen Undercurrent, a near‐bottom current that flows eastward along the shelf break and transports warm waters onto the continental shelf via troughs. Here we use a regional ice‐ocean model to show that, on decadal time scales, the undercurrent's variability is baroclinic (depth‐dependent). Decadal ocean surface cooling in the tropical Pacific results in cyclonic wind anomalies over the Amundsen Sea. These wind anomalies drive a westward perturbation of the shelf‐break surface flow and an eastward anomaly (strengthening) of the undercurrent, leading to increased ice‐shelf melting. This contrasts with shorter time scales, for which surface current and undercurrent covary, a barotropic (depth‐independent) behavior previously assumed to apply at all time scales. This suggests that interior ocean processes mediate the decadal ice‐shelf response in the Amundsen Sea to climate forcing.
No related grants have been discovered for Laychiluh Bantie Mekonnen.