Amongst males, leukaemia is the most common cause of cancer-related death in individuals younger than 40 years of age whereas in female children and adolescents, leukaemia is the most common cause of ...cancer-related death. Chronic myeloid leukaemia (CML) is a chronic leukaemia of the haematopoietic stem cells affecting mostly adults. The disease results from a translocation of the Philadelphia chromosome in stem cells of the bone marrow. CML patients usually present with mild to moderate anaemia and with decreased, normal, or increased platelet counts. CML represents 0.5% of all new cancer cases in the United States (2016). In 2016, an estimated 1070 people would die of this disease in the United States. Platelets serve as a means for tumours to increase growth and to provide physical- and mechanical support to elude the immune system and to metastasize. Currently there is no literature available on the role that platelets play in CML progression, despite literature reporting the fact that platelet count and size are affected. Resistance to CML treatment with tyrosine kinase inhibitors can be as a result of acquired resistance ensuing from mutations in the tyrosine kinase domains, loss of response or poor tolerance. In CML this resistance has recently become linked to bone marrow (BM) angiogenesis which aids in the growth and survival of leukaemia cells. The discovery of the lungs as a site of haematopoietic progenitors, suggests that CML resistance is not localized to the bone marrow and that the mutations leading to the disease and resistance to treatment may also occur in the haematopoietic progenitors in the lungs. In conclusion, platelets are significantly affected during CML progression and treatment. Investigation into the role that platelets play in CML progression is vital including how treatment affects the cell death mechanisms of platelets.
Decaprenylphosphoryl-b-d-ribose 20-epimerase (DprE1) is a potential drug target for development of antitubercular agents. Structure based drug discovery approach yielded twenty novel derivatives of ...benzothiazolylpyrimidine-5-carboxamides (7a–t) which were synthesised by three component one pot reaction involving benzothiazolyl oxobutanamide, thiourea and substituted aromatic benzaldehydes. These derivatives were evaluated for antitubercular activity to determine MIC and compound 7a, 7e, 7f and 7o were found to be potentially active against Mycobacterium tuberculosis (H37Rv). Log P of these compounds was found to be between 2.0 and 3.0 making them suitable for oral dosing. DprE1 selectivity and pharmacokinetic studies were carried out for these compounds of which 7a and 7o were found to be highly selective and bioavailability was found to be above 52% by oral dose. Crystal structure of 7a was studied and molecular packing was determined, it exhibited a triclinic crystal lattice arrangement having hydrogen bonded dimeric arrangement. Drug receptor interactions were studied which exhibited docking in the active site of receptor with hydrogen bonding, hydrophobic interactions, vdW interactions with amino acid residues such as Cys387, Asn385, Lys418, Tyr314, Gln334 and Lys367 respectively. 3D QSAR analysis was carried out by kNN-MFA method to determine and develop theoretical model, best suitable model was found to be based on Simulated Annealing k-Neariest Neighbour Molecular Field Analysis (SA kNN-MFA). The model provided with hydrophobic descriptors in positive side indicating the need of bulky groups, steric and electronegative descriptors in negative coordinates hints with contribution by the electronegative substitutions as favourable and desirable moieties for enhancing the activity. The q2, q2_se and Pred_r2se were found to be 0.5000, 0.6404 and 1.0094 respectively. A pharmacophore model was generated which suggested for necessity of aromatic, aliphatic carbon centre and hydrogen bond donor for development of newer DprE1 selective inhibitors.
Display omitted
•SBDD method yielded 20 novel derivatives of benzothiazolylpyrimidine-5-carboxamides.•In vitro and in vivo methods identified 4 derivatives as selective DprE1 inhibitors.•Log P found to be between 2.0 and 3.0 and bioavailability above 52% on oral dosing.•MD simulations revealed important interacting residues and stability of complexes.•3D-QSAR by SA kNN-MFA method and pharmacophore modelling suggests for optimization.
Chronic myeloid leukaemia (CML) is a malignancy of the haematopoietic stem cells. The first line of treatment for CML, especially in developing countries, remains the first‐generation tyrosine kinase ...inhibitor, Imatinib. Patients with CML are frequently diagnosed with platelet abnormalities. However, the specific mechanism of platelet abnormalities in CML remains unclear and poorly understood. The aim of this study was therefore to determine the apoptotic profiles of CML patients ex vivo on platelets before and after treatment with Imatinib. Blood samples of healthy volunteers and CML patients at diagnosis and after 6 months treatment with Imatinib were collected. Platelet counts, viability and activation were determined. Results showed that CML patients' platelet counts were elevated upon diagnosis and these levels statistically significantly decreased after 6 months of treatment. Platelet activation was significantly increased after 6 months of treatment compared to levels at diagnosis (P‐value < .05). Similarly, platelet apoptosis was also increased after 6 months of treatment. Abnormalities in platelet functioning found in this study may partly be due to clonal proliferation of haematopoietic cells in CML patients, specifically of megakaryocyte precursors as well as the inhibition of platelet tyrosine kinase's and the inhibition of platelet‐derived growth factor.
Phosphonium tosylates have been investigated as solvents for the Diels–Alder reactions of isoprene with methyl acrylate, but-3-en-2-one and acrylonitrile. The reactions with oxygen-containing ...dienophiles showed high regioselectivity.
Graphic
The manuscript describes design and synthesis of novel oxadiazolyl-2-oxoindolinylidene propane hydrazides as amide tethered hybrids of indole and oxadiazole and their evaluation for anti-inflammatory ...and analgesic activity. The compounds were synthesized following five step reaction to yield fifteen derivatives as 3-(5-substituted-1,3,4-oxadiazol-2-yl)-N'-2-oxo-1,2-dihydro-3H-indol-3-ylidenepropane hydrazides. The final derivatives 3-5-(4-hydroxyphenyl)-1,3,4-oxadiazol-2-yl-N'-2-oxo-1,2-dihydro-3H-indol-3-ylidenepropane hydrazide and 3-5-(4-methylphenyl)-1,3,4-oxadiazol-2-yl-N'-2-oxo-1,2-dihydro-3H-indol-3-ylidenepropane hydrazide were found to be highly promising molecules with severity index of 0.35 and 0.56, respectively, which is promising for an analgesic compound. The hydroxy and methyl substitution on phenyl ring system provided with active anti-inflammatory compounds having increase in reaction time of 84.11 and 83.17%, respectively compared to standard drug at 85.84%. Molecular docking studies exhibit comparable interaction with synthesized derivatives and standard drug having a dock score of -4.44 by the K-nearest neighbour genetic algorithm method.
Display omitted
L-type voltage gated calcium channels play essential role in contraction of various skeletal and vascular smooth muscles, thereby plays important role in regulating blood pressure. ...Dihydropyridine receptors have been targeted for development of newer antihypertensive agents, one of the structurally analogs nucleus dihydropyrimidines have been reported earlier by us as a potential agent toward development of calcium channel modulator. A pre-synthetic QSAR was run and on the basis of structure activity relationship a series of twenty three molecules was synthesized and studied by myosin light chain kinase assay (MLCK), Angiotensin Converting Enzyme (ACE) colorimetric assay, non-invasive blood pressure (NIBP) and invasive blood pressure (IBP) methods. Molecules with significant efficacy were studied for their single crystal X-ray diffraction, molecular docking, molecular dynamics and post-synthetic QSAR. The NIBP and IBP methods screened molecules with better percentage inhibition versus time compared to standard drug Nifedipine. The lead compound ethyl 2-methyl-4-(3-nitrophenyl)-4H-pyrimido 2,1-b 1,3 benzothiazole-3-carboxylate (26) presented a triclinic structure with polymeric chain packing in lattice. 26 exhibited IC50on MLCK assay of 2.1±1.7μM with selectivity of L-type calcium channels and comparative to Nifedipine. It offered satisfactory physicochemical properties with partition coefficient of (ClogP) 4.64. Its pharmacokinetic profile is also good with Cmax at 0.40μg/ml by oral route with Tmax reaching in 0.5h which means in 30min. 26 also exhibits superior t1/2 of 5.4h and oral bioavailability of (F) 56.75% with an AUC0–∞ of 0.84μgh/ml. Molecular docking studies indicates toward the interaction of lead compound via hydrogen bonds with Lys144, Glu181 and Asp183, it forms the Van der Walls interactions with Ser18, Asp20, Asn187, Pro185, Glu180, Glu181 and Arg10 with Glide score and Glide energy to be −3.602 and −47.098, respectively. Post-synthetic QSAR of newly synthesized molecules indicates toward improvement with respect to steric descriptor which contributed negatively in former series.
Background: In 2020, the World Health Organisation (WHO) declared Covid-19 as a pandemic. In South Africa, on 24 March 2020, the president of the Republic of South Africa announced that the country ...would be placed in a total lockdown from 27 March 2020 in which no persons were allowed to operate businesses unless they were healthcare workers or in some other essential business concerns. As set out in an extraordinary policy decision of the executive committee of the Allied Health Professions Council of South Africa (AHPCSA) of 25 March 2020, AHPCSA-regulated practitioners and therapists were able to receive patients using a telehealth/ telemedicine modus, this decision suspending a previous AHPCSA 2011 decision which disallowed the practice. In clarification of the AHPCSA executive committee extraordinary policy decision, the AHPCSA Registrar issued a notification on 26 March 2020 indicating that patients could be received, but in essential cases only, namely in emergencies only, at the registered place of practice on a face-to face basis. In all other cases, the reception of patients was required in terms of the telehealth/telemedicine modus according to the AHPCSA published Telehealth and Telemedicine Guidelines. The restriction on receiving patients in cases of emergency only was lifted on 1 May 2020 pursuant to a subsequent extraordinary AHPCSA executive committee policy decision on 29 April 2020, but the AHPCSA Telehealth and Telemedicine Guidelines remain in force for AHPCSA-regulated practitioners and therapists to receive patients. The research question must then consider whether these AHPCSA Guidelines included similar recommendations to those of other countries, and if these Guidelines could be supported by published literature. It remains important that, despite the method of practice used, Chiropractic care is required to ensure that the fundamental rights of patients were still respected, namely those of dignity, privacy, confidentiality and informed consent.Aim:The aim of the study was to analyze the AHPCSA Telehealth and Telemedicine guidelines recommended in response to the Covid-19 pandemic. This qualitative, descriptive study design used document analysis to conduct an in-depth analysis of the AHPCSA Telehealth and Telemedicine Guidelines published in other countries as well as published literature in other healthcare fields.To achieve this aim, the following objectives used were:1.2.1 Compare AHPCSA Telehealth and Telemedicine Guidelines to the guidelines that have been published by other Chiropractic associations worldwide.1.2.2 Use published literature in other healthcare fields to test the Telehealth and Telemedicine requirements in the AHPCSA guidelines.Method: This is a qualitative, descriptive study design using document analysis as described by Bowen (2009) to conduct an in-depth analysis of the AHPCSA Telehealth and Telemedicine Guidelines. Documents used included guidelines published by other Chiropractic associations worldwide, as well as literature published on Telehealth and Telemedicine in other healthcare disciplines. This research method allowed for documents to be selected with regard to telehealth and telehealth communications guidelines set out for chiropractors around the world which was accessed across the following sources: PubMed, Science Direct, EBSCOhost, Wiley Online Library and SpringerLin. This in turn allowed for the development of themes and sub-themes that were identified within this research study.
This thesis presents lifetime measurements of charmless two-body decays of b hadrons, specifically the decay modes known as B->hh', where B refers to meson or baryon containing a b quark and h' ...refers to a proton p, pion pi or kaon K. Using the large data samples collected by the LHCb detector, the \BTohh channels with the largest branching fractions provide an opportunity to perform high-precision measurements of the properties of the decays. The leading-order processes in B->hh' decays are tree and penguin topologies, where the loop-dominated channels could be sensitive to non-standard model physics. The Bs->KK mode is particularly interesting as it has a CP-even final state, as well as being dominated by penguin decay processes. The Bs->KK effective lifetime can be used to calculate the Bs decay-rate asymmetry A_{\Delta \Gamma}, which quantifies the amount of CP violation in the decay. Using LHCb data with an integrated luminosity of 3 fb{-1} collected at centre of mass energies of 7 TeV and 8 TeV, the lifetimes of the decays Bs->KK, Bd->Kpi, Bs->piK, Bd->pipi, Lambda_b->ppi and Lambda_b->pK are measured to be tau_{Bs->KK} = 1.410 +\- 0.009 ps (stat) +\- 0.011 ps (syst), tau_{Bd->Kpi} = 1.504 +\- 0.006 ps (stat) +\- 0.023 ps (syst), tau_{Bs->piK} = 1.548 +\- 0.028 ps (stat) +\- 0.023 ps (syst), tau_{Bd->pipi} = 1.495 +\- 0.012 ps (stat) +\- 0.007 ps (syst), tau_{Lambda_b->ppi} = 1.511 +\- 0.028 ps (stat) +\- 0.012 ps (syst), tau_{Lambda_b->pK} = 1.477 +\- 0.022 ps (stat) +\- 0.022 ps (syst). All these lifetime measurements are compatible with the current world averages. The decay-rate asymmetry is calculated to be A_{\Delta \Gamma}= -0.975 +\- 0.092 (stat) +\- 0.113 (syst) \pm 0.082 (ext), which agrees with the standard model prediction. A performance study measuring the photoelectron yield of the Ring Imaging Cherenkov (RICH) subdetector during 2012, 2015 and 2016 is also presented in this thesis. The RICH is used for particle identification and it distinguishes between pion, kaon and proton tracks. During the long shutdown between the 2012 and 2015 data taking periods, the aerogel in the RICH 1 detector was removed and the centre-of-mass energies of the proton-proton collisions increased from 7-8 TeV to 13 TeV. The photoelectron yield of RICH 1 was found to increase by ~3 photoelectrons in 2015 and 2016 and the photoelectron yield of RICH2 remained the same. This increase in RICH1 was expected due to the increased path length of the tracks through the Cherenkov medium once the aerogel was removed. Overall the contribution of photoelectron yield to the performance of the RICH remains acceptable for continued data taking.
This thesis presents lifetime measurements of charmless two-body decays of b hadrons, specifically the decay modes known as B->hh', where B refers to meson or baryon containing a b quark and h' ...refers to a proton p, pion pi or kaon K. Using the large data samples collected by the LHCb detector, the \BTohh channels with the largest branching fractions provide an opportunity to perform high-precision measurements of the properties of the decays. The leading-order processes in B->hh' decays are tree and penguin topologies, where the loop-dominated channels could be sensitive to non-standard model physics. The Bs->KK mode is particularly interesting as it has a CP-even final state, as well as being dominated by penguin decay processes. The Bs->KK effective lifetime can be used to calculate the Bs decay-rate asymmetry A_{\Delta \Gamma}, which quantifies the amount of CP violation in the decay. Using LHCb data with an integrated luminosity of 3 fb^{-1} collected at centre of mass energies of 7 TeV and 8 TeV, the lifetimes of the decays Bs->KK, Bd->Kpi, Bs->piK, Bd->pipi, Lambda_b->ppi and Lambda_b->pK are measured to be tau_{Bs->KK} = 1.410 +\- 0.009 ps (stat) +\- 0.011 ps (syst), tau_{Bd->Kpi} = 1.504 +\- 0.006 ps (stat) +\- 0.023 ps (syst), tau_{Bs->piK} = 1.548 +\- 0.028 ps (stat) +\- 0.023 ps (syst), tau_{Bd->pipi} = 1.495 +\- 0.012 ps (stat) +\- 0.007 ps (syst), tau_{Lambda_b->ppi} = 1.511 +\- 0.028 ps (stat) +\- 0.012 ps (syst), tau_{Lambda_b->pK} = 1.477 +\- 0.022 ps (stat) +\- 0.022 ps (syst). All these lifetime measurements are compatible with the current world averages. The decay-rate asymmetry is calculated to be A_{\Delta \Gamma}= -0.975 +\- 0.092 (stat) +\- 0.113 (syst) \pm 0.082 (ext), which agrees with the standard model prediction. A performance study measuring the photoelectron yield of the Ring Imaging Cherenkov (RICH) subdetector during 2012, 2015 and 2016 is also presented in this thesis. The RICH is used for particle identification and it distinguishes between pion, kaon and proton tracks. During the long shutdown between the 2012 and 2015 data taking periods, the aerogel in the RICH 1 detector was removed and the centre-of-mass energies of the proton-proton collisions increased from 7-8 TeV to 13 TeV. The photoelectron yield of RICH 1 was found to increase by ~3 photoelectrons in 2015 and 2016 and the photoelectron yield of RICH2 remained the same. This increase in RICH1 was expected due to the increased path length of the tracks through the Cherenkov medium once the aerogel was removed. Overall the contribution of photoelectron yield to the performance of the RICH remains acceptable for continued data taking.
BACKGROUND: The discharge of synthetic dyes by the textile industry into the environment poses concerns due to their persistence and toxicity. New efficient treatment processes are required to ...effectively degrade these dyes. The aim of this work was to study the degradation of a persistent dye (Drimarene Brilliant Reactive Red K-4BL, C.I.147) using H₂O₂ oxidation catalysed by an Mn(III)-saltren catalyst and to develop a kinetic model for this system.RESULTS: Dye oxidation with H₂O₂ was significantly improved by the addition of the catalyst. As the pH was increased from 3 to 10, the oxidation rates increased significantly. The kinetic model developed in this study was found to adequately explain the experimental results. In particular, dye oxidation can be described at high pH by pseudo-first-order kinetics. A Michaelis-Menton type equation was developed from the model and was found to adequately describe the effect of H₂O₂ and catalyst concentrations on the apparent pseudo-first-order rate constant. Optimum catalyst and H₂O₂ concentrations of 500 mg L⁻¹ and 6.3 g L⁻¹, respectively, were found to give maximum reaction rates.CONCLUSION: Catalytic H₂O₂ oxidation was found to be effective for the removal of persistent dye and the results obtained in this work are of significance for design and scale-up of a treatment process. Copyright
PDF
