15 research outputs found
Comparison in the incidence of anorectal malformations between a first- and third-world referral center
PURPOSE : Aim of study was to evaluate the differences in
incidence and presentation of anorectal malformations
(ARMs) between selected Pediatric Surgery Divisions in
the Republic of South Africa (ZAR) and Italy.
METHODS : A retrospective cohort study involved analysis
of clinical records of patients with ARM born between
2005 and 2012. Type of ARM, maternal age, birth weight,
gestational age, presence of associated anomalies and
delayed diagnosis were analyzed.
RESULTS : 335 patients were included in this study. Of note,
statistically significant differences between the African and
European patient groups were observed in a male predominance
in the ZAR patient population. In addition,
female recto-perineal fistulas were diagnosed in significantly
more Italian patients than in ZAR. Furthermore, a
more advanced maternal age and a lower gestational age
was noted in the European cohort with a minimal delay in
initial diagnosis as opposed to the African counterpart.
Both centers reported recto-perineal fistula as the most
common malformation in male patients.
CONCLUSION : With the exception of perineal fistulas in
females, the incidence of specific subtypes of ARMs was similar in the two groups. This may be of importance when
extrapolating European study conclusion to the South
African setting.http://link.springer.com/journal/3832016-08-31hb201
Autophagy induced by a sulphamoylated estrone analogue contributes to its cytotoxic effect on breast cancer cells
BACKGROUND : Autophagy can either be protective and confer survival to stressed cells, or it can contribute to cell
death. The antimitotic drug 2-ethyl-3-O-sulpamoyl-estra-1,3,5(10),15-tetraen-17-ol (ESE-15-ol) is an in silico-designed
17-ÎČ-estradiol analogue that induces both autophagy and apoptosis in cancer cells. The aim of the study was to
determine the role of autophagy in ESE-15-ol-exposed human adenocarcinoma breast cancer cells; knowledge that
will contribute to future clinical applications of this novel antimitotic compound. By inhibiting autophagy and determining
the cytotoxic effects of ESE-15-ol-exposure, deductions could be made as to whether the process may confer
resistance to the drug, or alternatively, contribute to the cell death process.
METHODS AND RESULTS : Spectophometrical analysis via crystal violet staining was used to perform cytotoxicity studies.
Morphology studies were done using microscopic techniques namely polarization-optical transmitted light differential
interference light microscopy, fluorescent microscopy using monodansylcadaverine staining and transmission
electron microscopy. Flow cytometry was used to quantify the autophagy inhibition and assess cell viability. Results
obtained indicated that 3-methyladenine inhibited autophagy and increased cell survival in both MCF-7 and MDAMB-
231 cell lines.
CONCLUSION : This in vitro study inferred that autophagy inhibition with 3-methyladenine does not confer increased
effectiveness of ESE-15-ol in inducing cell death. Thus it may be concluded that the autophagic process induced by
ESE-15-ol exposure in MCF-7 and MDA-MB-231 cells plays a more significant role in cell death than conferring survival.Grants from the Medical Research Council of South Africa, the
Cancer Association of South Africa, National Research Foundation and the
Struwig-Germeshuysen Cancer Research Trust of South Africa.http://www.cancerci.comam2017Physiolog
Modes of cell death induced by tetrahydroisoquinoline-based analogs in MDA-MB-231 breast and A549 lung cancer cell lines
BACKGROUND : A and B rings of the steroidal microtubule disruptor, 2-methoxyestradiol, and its analogs can be mimicked with a tetrahydroisoquinoline (THIQ) core. THIQs are cytotoxic agents with potential anticancer activities. The aim of this in vitro study was to investigate the modes of cell death induced by four nonsteroidal THIQ-based analogs, such as STX 2895, STX 3329, STX 3451 and STX 3450, on MDA-MB-231 metastatic breast and A549 epithelial lung carcinoma cells.
MATERIALS AND METHODS : Cytotoxicity studies determined the half-maximal growth inhibitory concentration of the analogs to be at nanomolar concentrations without the induction of necrosis. Light and fluorescent microscopy determined that compounds caused microtubule depolymerization and displayed morphological hallmarks of apoptosis.
RESULTS : Flow cytometric analyses confirmed apoptosis induction as well as an increased G2/M phase on cell cycle analysis. Furthermore, intrinsic pathway signaling was implicated due to increased cytochrome c release and a decrease in mitochondrial transmembrane potential. Potential involvement of autophagy was observed due to increased acidic vacuole formation and increased aggresome activation factor.
CONCLUSION : Thus, it can be concluded that these four THIQ-based analogs exert anti-
proliferative and antimitotic effects, induce apoptosis and involve autophagic processes. Further investigation into the efficacy of these potential anticancer drugs will be conducted in vitro and in vivo.The abstract of this paper was presented at the 24 Biennial Congress of the European Association for Cancer Research, July 9â12, 2016, Manchester, UK, and was published in the European Journal of Cancer.Grants from the Medical Research Council of South Africa, the Cancer Association of South Africa, National Research Foundation and the Struwig-Germeshuysen Cancer Research Trust of South Africa. BVLP is a Wellcome Trust Senior Investigator (grant 101010).http://www.dovepress.com/drug-design-development-and-therapy-journalam2018Physiolog
Antimitotic drugs in the treatment of cancer
Cancer is a complex disease since it is adaptive
in such a way that it can promote proliferation and
invasion by means of an overactive cell cycle and in turn
cellular division which is targeted by antimitotic drugs
that are highly validated chemotherapy agents. However,
antimitotic drug cytotoxicity to non-tumorigenic cells and
multiple cancer resistance developed in response to drugs
such as taxanes and vinca alkaloids are obstacles faced in
both the clinical and basic research field to date. In this
review, the classes of antimitotic compounds, their mechanisms
of action and cancer cell resistance to chemotherapy
and other limitations of current antimitotic compounds are
highlighted, as well as the potential of novel 17-ÎČ estradiol
analogs as cancer treatment.Medical Research Council of South Africa, the Research Committee of the Faculty of Health Sciences of the University of Pretoria, the Cancer association of South Africa and the National Research Foundation.http://link.springer.com/journal/280hb201
Molecular crosstalk between apoptosis and autophagy induced by a 2-methoxyestradiol analogue (C19) in HeLa cells
Using a novel synthesised sulphamoylated 2-methoxyestradiol
analogue, C19, two types of cell death, namely apoptosis and autophagy, were demonstrated
in vitro when cervical cancer HeLa cells were exposed to this compound.http://www.satnt.ac.z
Novel in silico-designed estradiol analogues are cytotoxic to a multidrug-resistant cell line at nanomolar concentrations
PURPOSE : 2-Methoxyestradiol (2ME) is a promising anticancer
agent that disrupts the integrity and dynamics of the
spindle network. In order to overcome the pharmacokinetic
constraints of this compound, a panel of sulphamoylated
estradiol analogues were in silico-designed by our laboratory.
In this study, we analysed the potential of each analogue
to induce cell death on a panel of cancer cell lines.
Moreover, the mechanism of action of the most effective
compounds was determined.
METHODS : Cytotoxicity screening of the compounds and
intermediates was performed on five different cancer cell
lines to determine IG50 values. An in vitro tubulin polymerization
assay was done to determine the effect of the drugs
on tubulin polymerization while their intracellular effects
on the microtubule network were assessed by immunofluorescence
microscopy.
RESULTS : IG50 calculations showed that the sulphamoylated
analogues induce cytotoxicity at nanomolar concentrations
in all cell lines, including the P-glycoprotein pump overexpressing multidrug-resistant uterine sarcoma cell
line. The non-sulphamoylated compounds were only cytotoxic
at micromolar ranges, if at all. The sulphamoylated
compounds inhibited pure tubulin polymerization in a
dose-dependent manner and induced microtubule destruction
in cells after 24-h exposure.
CONCLUSION : Results revealed that the novel sulphamoylated
2ME derivatives have potential as anti-cancer
drugs, possibly even against chemoresistant cancer cells.
These compounds disrupt the intracellular microtubule
integrity which leads to mitotic block of the cells.The Research Development Programme of the University of Pretoria (RDP AOV840), the South African Medical Association (SAMA), the National Research Foundation (NRF Project # 86475, N00465, N00375, N00591), the Research Committee of the Faculty of Health Sciences, University of Pretoria (RESCOM), CANSA (AOV741, AOW228) and the Medical Research Council (MRC AOW110).http://link.springer.com/journal/2802016-02-28hb201
Large expert-curated database for benchmarking document similarity detection in biomedical literature search
Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe
Molecular crosstalk between apoptosis and autophagy induced by a 2-methoxyestradiol analogue (C19) in HeLa cells
Cervical cancer is reported by the World Health Organisation to be the second most
common type of cancer to affect women in poorer socioeconomic countries. Treatment of
this pathology remains sub-optimal at advanced stages and continues to be of importance
on the research agenda.
Previous studies have reported cytotoxic and antiproliferative effects of 2-methoxyestradiol
(2-ME) in vitro on a HeLa cervical cancer cell line. These results were promising but use of
2-ME itself is limited due to pharmacodynamic constraints. In an attempt to overcome
these, a sulphamoylated analogue of 2-ME, namely 2-ethyl-3-O-sulphamoyl-estra-
1,3,5(10)16-tetraene or compound 19 (C19), was synthesised.
In this in vitro study, the induction of a block in mitosis with subsequent culmination of
apoptosis and autophagy as types of cells death was investigated after HeLa cells were
exposed for 24 hours to a 0.5 ÎŒM C19 solution. This was achieved by morphological
assessment (fluorescent, Polarization-optical transmitted light differential interference
contrast microscopy (PlasDIC) and transmission electron microscopy (TEM)) and flow
cytometry (cell cycle progression, cyclin B1 analysis, phosphatidylserine (PS) flip and
aggresome formation). Spectrophotometric quantification of the apoptotic initiator and
executioner caspases 8 and 3 respectively was done to determine their involvement in the
crosstalk between apoptosis and autophagy.
Results included the following: (i) PlasDIC microscopy illustrated the appearance of an
increased number of cells blocked in metaphase, stress signaling, premature cell shrinkage,
hypercondensed chromatin and the presence of apoptotic bodies after C19 exposure. The
presence of ghost cells, cell debris and decreased cell density of the treated cells correlated
with the autophagy control. (ii) Fluorescence microscopy employing triple staining
highlighted an increased lysosomal activity and staining of C19-exposed cells when
compared to the control, as well as evidence of apoptotic and metaphase-blocked cells. This is indicative of both the autophagic and apoptotic cell death process. (iii) TEM allowed
for examination of the ultrastructure of the intracellular processes, and revealed that
apoptotic cells have hallmarks of both autophagy and apoptosis, confirming the results of
light microscopy. (iv) Cell cycle analysis demonstrated more cells present in the sub-G1 and
G2/M populations, indicating the induction of apoptosis (confirmed with PS fip flow
cytometric quantification) and a metaphase block (corroborated by an increased cyclin B1
fluorescence). (v) The increase in autophagosome formation seen on fluorescence- and
transmission electron microscopy was confirmed by flow cytometry demonstrating an
upregulation of aggresome formation in C19-exposed cells. This investigation
demonstrated induction of both types of cells death by this novel compound. (vi) The
upregulation of caspases 8 and 3 was demonstrated in the C19-treated cells, indicating
apoptosis induction via the extrinsic pathway. (vii) Confocal microscopy demonstrated
complete microtubule disintegration in the C19-exposed HeLa cells.
Both apoptotic and autophagic cell death mechanisms were induced in C19-treated HeLa
cells after spindle abrogation kept the cells in metaphase block. Insight gained into the
molecular effect of C19 on HeLa cells may be used as a springboard for in vivo studies,
furthering the development of this promising anticancer agent toward clinical application.Dissertation (MSc)--University of Pretoria, 2012.PhysiologyMScUnrestricte
Developing national obesity prevention policies: an international perspective
La progression de lâobĂ©sitĂ© en France se confirme Ă travers une sĂ©rie dâĂ©tudes
Ă©pidĂ©miologiques concordantes chez lâenfant comme chez lâadulte. Des
mesures prĂ©ventives sâimposent. Le systĂšme de soins doit rĂ©pondre Ă ce
nouvel enjeu.
Aujourdâhui, la question nâest plus celle du bien-fondĂ© de programmes de
santĂ© publique pour lutter contre lâobĂ©sitĂ© mais celle de leur conception, de
leur application, de leur pérennité et de leur évaluation.
La recherche dâune cohĂ©rence entre les programmes de santĂ© publique et les
politiques publiques, en particulier dans le domaine de lâagro-alimentaire, de
lâamĂ©nagement urbain et de la communication nutritionnelle est essentielle.(...)229 pages, tableaux, graphiques, figure
Thrombotic and hemorrhagic complications of COVID-19 in adults hospitalized in high-income countries compared with those in adults hospitalized in low- and middle-income countries in an international registry
Background: COVID-19 has been associated with a broad range of thromboembolic, ischemic, and hemorrhagic complications (coagulopathy complications). Most studies have focused on patients with severe disease from high-income countries (HICs). Objectives: The main aims were to compare the frequency of coagulopathy complications in developing countries (low- and middle-income countries [LMICs]) with those in HICs, delineate the frequency across a range of treatment levels, and determine associations with in-hospital mortality. Methods: Adult patients enrolled in an observational, multinational registry, the International Severe Acute Respiratory and Emerging Infections COVID-19 study, between January 1, 2020, and September 15, 2021, met inclusion criteria, including admission to a hospital for laboratory-confirmed, acute COVID-19 and data on complications and survival. The advanced-treatment cohort received care, such as admission to the intensive care unit, mechanical ventilation, or inotropes or vasopressors; the basic-treatment cohort did not receive any of these interventions. Results: The study population included 495,682 patients from 52 countries, with 63% from LMICs and 85% in the basic treatment cohort. The frequency of coagulopathy complications was higher in HICs (0.76%-3.4%) than in LMICs (0.09%-1.22%). Complications were more frequent in the advanced-treatment cohort than in the basic-treatment cohort. Coagulopathy complications were associated with increased in-hospital mortality (odds ratio, 1.58; 95% CI, 1.52-1.64). The increased mortality associated with these complications was higher in LMICs (58.5%) than in HICs (35.4%). After controlling for coagulopathy complications, treatment intensity, and multiple other factors, the mortality was higher among patients in LMICs than among patients in HICs (odds ratio, 1.45; 95% CI, 1.39-1.51). Conclusion: In a large, international registry of patients hospitalized for COVID-19, coagulopathy complications were more frequent in HICs than in LMICs (developing countries). Increased mortality associated with coagulopathy complications was of a greater magnitude among patients in LMICs. Additional research is needed regarding timely diagnosis of and intervention for coagulation derangements associated with COVID-19, particularly for limited-resource settings