Purpose
Cancer cells often elicit a higher glycolytic rate than normal cells, supporting the development of glycolysis inhibitors as therapeutic agents. 2-Deoxyglucose (2-DG) is used in this context ...due to its ability to compete with glucose. However, many studies do not take into account that 2-DG inhibits not only glycolysis but also N-glycosylation. Since there are limited publications on 2-DG mechanism of action in breast cancer, we studied its effects in breast cancer cell lines to determine the part played by glycolysis inhibition and N-linked glycosylation interference.
Methods and Results
2-Deoxyglucose behaved as an anticancer agent with a similar efficiency on cell number decrease between the hormone-dependent MCF-7 and hormone-independent MDA-MB-231 breast cancer cells. It also interfered with the N-linked glycosylation process in both cell lines as illustrated by the migration profile of the lysosomal-associated membrane protein 2 and calumenin. These results are reinforced by the appearance of an abnormal Man7GlcNAc2 structure both on lipid-linked oligosaccharides and N-linked glycoproteins of 2-DG incubated MDA-MB-231 cells. Besides, 2-DG-induced a transient endoplasmic reticulum stress that was more sustained in MDA-MB-231 cells. Both changes were abrogated by mannose. 2-DG, even in the presence of mannose, decreased glycolysis in both cell lines. Mannose partially reversed the effects of 2-DG on cell numbers with N-linked glycosylation interference accounting for 37 and 47% of 2-DG anti-cancerous effects in MDA-MB-231 and MCF-7 cells, respectively.
Conclusion
N-linked glycosylation interference and glycolysis disruption both contribute to the anticancer properties of 2-DG in breast cancer cells.
The metabolism of cancer cells generally differs from that of normal cells. Indeed, most cancer cells have a high rate of glycolysis, even at normal oxygen concentrations. These metabolic properties ...can potentially be exploited for therapeutic intervention. In this context, we have developed troglitazone derivatives to treat hormone-sensitive and triple-negative breast cancers, which currently lack therapeutic targets, have an aggressive phenotype, and often have a worse prognosis than other subtypes. Here, we studied the metabolic impact of the EP13 compound, a desulfured derivative of Δ2-troglitazone that we synthetized and is more potent than its parent compounds.
EP13 was tested on two triple-negative breast cancer cell lines, MDA-MB-231 and Hs578T, and on the luminal cell line MCF-7. The oxygen consumption rate (OCR) of the treated cell lines, Hs578T mammospheres and isolated mitochondria was measured using the XFe24 Seahorse analyser. ROS production was quantified using the MitoSOX fluorescent probe. Glycolytic activity was evaluated through measurement of the extracellular acidification rate (ECAR), glucose consumption and lactate production in extracellular medium. The synergistic effect of EP13 with glycolysis inhibitors (oxamate and 2-deoxyglucose) on cell cytotoxicity was established using the Chou-Talalay method.
After exposure to EP13, we observed a decrease in the mitochondrial oxygen consumption rate in MCF7, MDA-MB-231 and Hs578T cells. EP13 also modified the maximal OCR of Hs578T spheroids. EP13 reduced the OCR through inhibition of respiratory chain complex I. After 24 h, ATP levels in EP13-treated cells were not altered compared with those in untreated cells, suggesting compensation by glycolysis activity, as shown by the increase in ECAR, the glucose consumption and lactate production. Finally, we performed co-treatments with EP13 and glycolysis inhibitors (oxamate and 2-DG) and observed that EP13 potentiated their cytotoxic effects.
This study demonstrates that EP13 inhibits OXPHOS in breast cancer cells and potentiates the effect of glycolysis inhibitors.
Breast cancer is a major medical threat which cannot be sufficiently addressed by current therapies because of spontaneous or acquired treatment resistance. Besides, triple-negative breast cancer ...(TNBC) tumors do not respond to targeted therapies, thus new therapeutic strategies are needed. In this context, we designed and prepared new desulfured troglitazone (TGZ)-derived molecules and evaluated them in vitro for their anti-proliferative activity, with a special focus on triple-negative breast cancer cell lines. Optimization of the synthetic strategies and deracemization of the lead compound were performed to give highly active compound 10 with low-micromolar potency. Further studies revealed that this compound triggers apoptosis rather than cell cycle arrest as observed with TGZ.
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•New desulfured troglitazone derivatives were prepared with improved chemical synthesis and a deracemization strategy.•Their pro-apoptotic activity was evaluated against breast cancer cell lines.•Further biological studies revealed that the lead compound is a powerful pro-apoptotic agent.
Background and purpose
Susac syndrome (SuS) is an inflammatory condition of the brain, eye and ear. Diagnosis can be challenging, and misdiagnosis is common.
Methods
This is a retrospective review of ...the medical records of 32 adult patients from an Australasian cohort of SuS patients.
Results
An alternative diagnosis prior to SuS was made in 30 patients (94%) with seven patients receiving two or more diagnoses. The median time to diagnosis of SuS was 3 months (range 0.5–100 months). The commonest misdiagnoses were migraine in 10 patients (31%), cerebral vasculitis in six (19%), multiple sclerosis in five (16%) and stroke in five (16%). Twenty‐two patients were treated for alternative diagnoses, 10 of whom had further clinical manifestations prior to SuS diagnosis. At presentation seven patients (22%) met criteria for definite SuS, 19 (59%) for probable SuS and six (19%) for possible SuS. Six patients (19%) presented with brain–eye–ear involvement, 14 with brain–ear (44%), six with brain–eye (19%) and six (19%) with only brain involvement. In patients with the complete triad of symptoms the median delay to diagnosis was 3 months (range 1–9 months) compared to 5.25 months (range 0.5–100 months) for patients with encephalopathy and ocular symptoms at presentation.
Conclusions
Susac syndrome patients are frequently misdiagnosed at initial presentation, despite many having symptoms or radiological features that are red flags for the diagnosis. Delayed diagnosis can lead to patient morbidity. The varied ways in which SuS can present, and clinician failure to consider or recognize SuS, appear to be the main factors leading to misdiagnosis.
The delay to diagnosis of Susac syndrome was influenced by extent of brain, eye and ear involvement at presentation with the fastest diagnosis in patients with brain only involvement, and the slowest diagnosis in those with brain and eye involvement.
Endovascular thrombectomy (EVT) access in remote areas is limited. Preliminary data suggest that long distance transfers for EVT may be beneficial; however, the magnitude and best imaging strategy at ...the referring center remains uncertain. We hypothesized that patients transferred >300 miles would benefit from EVT, achieving rates of functional independence (modified Rankin Scale mRS score of 0-2) at 3 months similar to those patients treated at the comprehensive stroke center in the randomized EVT extended window trials and that the selection of patients with computed tomography perfusion (CTP) at the referring site would be associated with ordinal shift toward better outcomes on the mRS.
This is a retrospective analysis of patients transferred from 31 referring hospitals >300 miles (measured by the most direct road distance) to 9 comprehensive stroke centers in Australia and New Zealand for EVT consideration (April 2016 through May 2021).
There were 131 patients; the median age was 64 53-74 years and the median baseline National Institutes of Health Stroke Scale score was 16 12-22. At baseline, 79 patients (60.3%) had noncontrast CT+CT angiography, 52 (39.7%) also had CTP. At the comprehensive stroke center, 114 (87%) patients underwent cerebral angiography, and 96 (73.3%) proceeded to EVT. At 3 months, 62 patients (48.4%) had an mRS score of 0 to 2 and 81 (63.3%) mRS score of 0 to 3. CTP selection at the referring site was not associated with better ordinal scores on the mRS at 3 months (mRS median of 2 1-3 versus 3 1-6 in the patients selected with noncontrast CT+CT angiography,
=0.1). Nevertheless, patients selected with CTP were less likely to have an mRS score of 5 to 6 (odds ratio 0.03 0.01-0.19;
<0.01).
In selected patients transferred >300 miles, there was a benefit for EVT, with outcomes similar to those treated in the comprehensive stroke center in the EVT extended window trials. Remote hospital CTP selection was not associated with ordinal mRS improvement, but was associated with fewer very poor 3-month outcomes.
Background
As the prevalence of dementia increases, the need for appropriately trained and skilled care teams also increases. Staff attitudes towards people living with dementia have a significant ...impact on caregiving behaviours and staff and resident outcomes. Training within care settings is a potential way of improving staff attitudes towards residents in their care.
Objectives
This review aimed to (i) assess the effectiveness of psychosocial training in improving care staff attitudes towards dementia; and (ii) examine the content and focus of training.
Method
The review was conducted following PRISMA guidance and the protocol was registered on PROSPERO prior to conducting the review. A comprehensive search of peer‐reviewed literature was undertaken using CINAHL, Medline and PsycINFO from inception to March 2021. All papers were evaluated using a quality appraisal tool.
Results
Ten studies met inclusion criteria and were of variable quality. However, six studies found significant improvements in staff attitudes towards dementia following staff training. The studies varied in terms of training focus and included behavioural, communication and cognitive‐based approaches.
Conclusions
Staff training could be an effective method of improving staff attitudes towards dementia in care settings. Further research adopting high‐quality randomised controlled designs to further explore staff attitudes following psychosocial training would make a valuable contribution to the literature base.
Rationale
Post-stroke hyperglycemia occurs in up to 50% of patients presenting with acute ischemic stroke. It reduces the efficacy of thrombolysis, increases infarct size, and worsens clinical ...outcomes. Insulin-based therapies have generally not been beneficial in treating post-stroke hyperglycemia as they are difficult to implement, may cause hypoglycaemia, possibly increase mortality and worsen clinical outcomes. Exenatide may be a safer, simpler, and more effective alternative to insulin in acute ischemic stroke.
Design
TEXAIS is a three year, Phase 2, multi-center, prospective, randomized, open label, blinded end-point trial comparing exenatide to standard of care. It aims to recruit 528 patients with a primary end point of major neurological improvement at 7 days defined as a ≥8-point improvement in NIHSS score, or NIHSS 0–1. Secondary outcomes of hyper- and hypoglycaemia at 5 days and NIHSS and mRS at 90 days will be measured. The treatment arm will receive exenatide 5 µg subcutaneously twice daily. The control arm will receive standard stroke unit care. Continuous glucose monitors will track the dynamic variability of glucose.
Conclusion
TEXAIS aims to show that exenatide is safe and effective in the treatment of post-stroke hyperglycemia. It has been designed to be highly generalizable with an ability to enroll a large percentage of patients with acute ischemic stroke, regardless of admission blood glucose level, diabetes status, or stroke severity, with very low risk of hypoglycemia.
Trial registration: ClinicalTrials.gov/ANZCTR NTA1127
It is not certain whether the blade geometry of videolaryngoscopes, either a hyperangulated or Macintosh shape, affects glottic view, success rate and/or tracheal intubation time in patients with ...expected difficult airways. We hypothesised that using a hyperangulated videolaryngoscope blade would visualise a higher percentage of glottic opening compared with a Macintosh videolaryngoscope blade in patients with expected difficult airways.
We conducted an open-label, patient-blinded, randomised controlled trial in adult patients scheduled to undergo elective ear, nose and throat or oral and maxillofacial surgery, who were anticipated to have a difficult airway. All airway operators were consultant anaesthetists. Patients were allocated randomly to tracheal intubation with either hyperangulated (C-MAC D-BLADE™) or Macintosh videolaryngoscope blades (C-MAC™). The primary outcome was the percentage of glottic opening. First attempt success was designated a key secondary outcome.
We assessed 2540 adults scheduled for elective head and neck surgery for eligibility and included 182 patients with expected difficult airways undergoing orotracheal intubation. The percentage of glottic opening visualised, expressed as median (IQR range), was 89 (69-99 0-100)% with hyperangulated videolaryngoscope blades and 54 (9-90 0-100)% with Macintosh videolaryngoscope blades (p < 0.001). First-line hyperangulated videolaryngoscopy failed in one patient and Macintosh videolaryngoscopy in 12 patients (13%, p = 0.002). First attempt success rate was 97% with hyperangulated videolaryngoscope blades and 67% with Macintosh videolaryngoscope blades (p < 0.001).
Glottic view and first attempt success rate were superior with hyperangulated videolaryngoscope blades compared with Macintosh videolaryngoscope blades when used by experienced anaesthetists in patients with difficult airways.
BackgroundRecently proposed diagnostic criteria for iatrogenic cerebral amyloid angiopathy (iCAA) have sparked increased recognition of cases across the globe. Whilst these patients tend to have a ...tumultuous course, much like sporadic CAA, there is a high degree of variability. What is unique in this case is the breadth of clinicoradiological data available, including handwritten surgical notes from 1985. In retrospect, early imaging changes of what would ultimately lead to profound morbidity, were apparent 30 years after inoculation with cadaveric dural tissue. AimIn this case study we examine the clinicoradiological features of a case of probable iCAA and draw awareness to the presence of this disease in Australia. MethodsThis case was admitted under the care of the author at the Royal Brisbane and Women's Hospital (RBWH). Clinical details and data were gathered during the patient's care and consent for publication provided by the enduring power of attorney. ResultsThis 56-year-old female presented in 2018 with left hemiparesis, neglect, and dysarthria secondary to a large right frontal lobe intracerebral hemorrhage (ICH) without an underlying macrovascular cause. MRI brain demonstrated diffuse superficial siderosis assumed related to previous surgical interventions during the mid-1980s for a Chiari malformation and cervical syrinx. There was evidence of extensive white matter disease, discordant with her lack of cerebrovascular disease risk factors. Brain biopsy confirmed CAA. Archived surgical notes confirmed exposure to Lyodura in 1985 and 1986. Two decades of MRI data were available for review and illustrate the evolution of CAA, from normal post-operative findings to marked and unrecognized abnormalities 4 years prior to her first ICH. DiscussionThis is the first Australian case of probable iatrogenic CAA (iCAA) to have such extensive documentation of clinicoradiological evolution. It demonstrates the aggressive course iCAA can take and provides insights into early disease manifestations, relevant to the more common sporadic cases. A brief review of the history of commercial cadaveric tissue use in Australia highlights enormous changes in medical practice over the last 50 years. Awareness within Australia should be raised for this clinical phenomenon, and cases collated to contribute to the growing international pool of evidence.
Der Band vereint sprachhistorische Beiträge zu den Familiennamenlandschaften in den Grenzregionen von Luxemburg, Belgien, Deutschland und Frankreich, die aus sprachhistorischen, kontaktlinguistischen ...und kartographischen Perspektiven beleuchtet werden. Diese Artikelsammlung richtet sich damit sowohl an Sprachhistoriker wie auch an Kulturhistoriker.
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