Although the BTK inhibitor ibrutinib has transformed the management of patients with chronic lymphocytic leukemia (CLL), it does not induce substantial apoptosis in vitro, and as such the mechanisms ...underlying its ability to kill CLL cells are not well understood. Acalabrutinib, a more specific BTK inhibitor now in development, also appears to be highly effective in CLL, but the connection of its mechanism with CLL cell death is also unclear. Using dynamic BH3 profiling, we analyzed alterations in the function of the mitochondrial apoptotic pathway induced by ibrutinib and acalabrutinib. We studied CLL patient samples treated ex vivo with both drugs, as well as primary samples from CLL patients on clinical trials of both drugs. We found that BTK inhibition enhances mitochondrial BCL-2 dependence without significantly altering overall mitochondrial priming. Enhancement of BCL-2 dependence was accompanied by an increase in the pro-apoptotic protein BIM. In contrast, treatment with the selective BCL-2 inhibitor venetoclax enhanced overall mitochondrial priming without increasing BCL-2 dependence. Pre-treatment of CLL cells with either BTK inhibitor, whether ex vivo or in vivo in patients, enhanced killing by venetoclax. Our data suggest that BTK inhibition enhances mitochondrial BCL-2 dependence, supporting the ongoing development of clinical trials combining BTK and BCL-2 inhibition.
Interpretation as Hypothesis Davids, M. Fakhry
Journal of the American Psychoanalytic Association,
12/2023, Letnik:
71, Številka:
6
Journal Article
Recenzirano
Two distinct spaces can be seen as operating in a session—a private one in the analyst’s mind, where formulations take shape, and one shared between patient and analyst, in which interpretations are ...offered. By maintaining a focus on the here and now in the latter space, taking care to protect it from intrusions from the analyst’s theory except as hypotheses (in the form of interpretations derived from those formulations) aimed at eliciting unconscious responses that further the analytic inquiry, a basis for analytic work is established that aligns with ordinary scientific processes: theory is generated in the mind of the researcher, and hypotheses derived from it are tested systematically in a laboratory setting. Self-understanding that develops out of such an arrangement can then be seen as based on evidence, minimizing the role of suggestion. This line of thinking is illustrated with excerpts from the beginning of the analysis of a depressed patient. In developing areas of theory, when reliable evidence is particularly important, this way of working holds promise. In this case evidence was systematically gathered that led to the formulation of a model of internal racism.
Psychoanalysis and black lives Davids, M. Fakhry
International journal of psychoanalysis,
09/2020, Letnik:
101, Številka:
5
Journal Article
Recenzirano
This paper suggests that being black in a white majority world attracts powerful racist projections whose cumulative effect can be deeply traumatising, a problem that has not received due attention ...in mainstream psychoanalysis. This theme is developed through a description of how this difficulty, and the patient's inner response to it, came to light at the beginning of an analysis. The patient, who grew up as the only brown-skinned child in his white family and community, and without a father, suffered from a lifelong preoccupation with men's genitals. On the couch he experienced extreme bodily discomfort that he sought to relieve through violent sexual thrusting; the paper describes how the stance of negative capability was employed to investigate the dynamics underpinning this. This brought to light the patient's experience of racist projection and intolerance on the part of his objects, as well as his identification with them. The importance of recognising and naming these experiences, gradually and as evidence permits, are seen as central in engaging him. The paper ends by discussing how the analyst's blackness may have facilitated this development, and underlines the urgency of addressing the neglect of these matters in the mainstream of our largely white profession.
Neutrality remains a key concept underpinning the psychoanalytic attitude, but its operation in the clinical setting must be reconfigured if the countertransference is to be used as a source of data, ...conveyed by projective identification. Subjective responses thus mobilized in the analyst need to be processed before attention can return to the evenly suspended state, from which greater objectivity flows. Theory, internalized as part of the analyst's emotional learning, operates preconsciously in the session; in clinical work with racial matters this includes, crucially, familiarity with internal racism, of which a model is briefly described. These ideas are illustrated via two clinical vignettes in which these themes are traced.
Airborne transmission of SARS-CoV-2 aerosol remains contentious. Importantly, whether cough or breath-generated bioaerosols can harbor viable and replicating virus remains largely unclarified. We ...performed size-fractionated aerosol sampling (Andersen cascade impactor) and evaluated viral culturability in human cell lines (infectiousness), viral genetics, and host immunity in ambulatory participants with COVID-19. Sixty-one percent (27/44) and 50% (22/44) of participants emitted variant-specific culture-positive aerosols <10μm and <5μm, respectively, for up to 9 days after symptom onset. Aerosol culturability is significantly associated with lower neutralizing antibody titers, and suppression of transcriptomic pathways related to innate immunity and the humoral response. A nasopharyngeal Ct <17 rules-in ~40% of aerosol culture-positives and identifies those who are probably highly infectious. A parsimonious three transcript blood-based biosignature is highly predictive of infectious aerosol generation (PPV > 95%). There is considerable heterogeneity in potential infectiousness i.e., only 29% of participants were probably highly infectious (produced culture-positive aerosols <5μm at ~6 days after symptom onset). These data, which comprehensively confirm variant-specific culturable SARS-CoV-2 in aerosol, inform the targeting of transmission-related interventions and public health containment strategies emphasizing improved ventilation.
Hypericin, an extract from St John's Wort (Hypericum perforatum L.), is a promising photosensitizer in the context of clinical photodynamic therapy due to its excellent photosensitizing properties ...and tumoritropic characteristics. Hypericin-PDT induced cytotoxicity elicits tumor cell death by various mechanisms including apoptosis, necrosis and autophagy-related cell death. However, limited reports on the efficacy of this photomedicine for the treatment of melanoma have been published. Melanoma is a highly aggressive tumor due to its metastasizing potential and resistance to conventional cancer therapies. The aim of this study was to investigate the response mechanisms of melanoma cells to hypericin-PDT in an in vitro tissue culture model. Hypericin was taken up by all melanoma cells and partially co-localized to the endoplasmic reticulum, mitochondria, lysosomes and melanosomes, but not the nucleus. Light activation of hypericin induced a rapid, extensive modification of the tubular mitochondrial network into a beaded appearance, loss of structural details of the endoplasmic reticulum and concomitant loss of hypericin co-localization. Surprisingly the opposite was found for lysosomal-related organelles, suggesting that the melanoma cells may be using these intracellular organelles for hypericin-PDT resistance. In line with this speculation we found an increase in cellular granularity, suggesting an increase in pigmentation levels in response to hypericin-PDT. Pigmentation in melanoma is related to a melanocyte-specific organelle, the melanosome, which has recently been implicated in drug trapping, chemotherapy and hypericin-PDT resistance. However, hypericin-PDT was effective in killing both unpigmented (A375 and 501mel) and pigmented (UCT Mel-1) melanoma cells by specific mechanisms involving the externalization of phosphatidylserines, cell shrinkage and loss of cell membrane integrity. In addition, this treatment resulted in extrinsic (A375) and intrinsic (UCT Mel-1) caspase-dependent apoptotic modes of cell death, as well as a caspase-independent apoptotic mode that did not involve apoptosis-inducing factor (501 mel). Further research is needed to shed more light on these mechanisms.
Background
Creatinine-based glomerular filtration rate (GFR)
-
estimating equations frequently do not perform well in populations that differ from the development populations in terms of mean GFR, ...age, pathology, ethnicity, and diet. After first evaluating the performance of existing equations, the aim of this study was to demonstrate the utility of an in-house modification of the equations to better fit a specific population.
Methods
Estimated GFR using 8 creatinine-based equations was first compared to 2-sample
51
Cr-ethylenediaminetetra-acetic acid plasma clearance in non-cancer and cancer groups independently. The groups were then divided into development and validation sets. Using the development set data, the Microsoft® Excel SOLVER add-in was used to modify the parameters of 7 equations to better fit the data. Using the validation set data, the performance of the original and modified equations was compared.
Results
Two hundred fifty-six GFR measurements were performed in 160 children. GFR was overestimated in both groups (non-cancer 4.3–22.6 ml/min/1.73 m
2
, cancer 17.2–46.6 ml/min/1.73 m
2
). The root mean square error (RMSE) was 19.1–21.8 ml/min/1.73 m
2
(non-cancer) and 18.6–20.8 ml/min/1.73 m
2
(cancer). The
P
30
values were 49.1–73.0% (non-cancer) and 19.6–66.0% (cancer). Modifying the parameters of seven equations resulted in significant improvements in the
P
30
values in the non-cancer (65.0–85.0%) and cancer (79.6–87.8%) groups.
Conclusions
Modifying the parameters of pediatric GFR estimating-equations using a simple Excel-based tool significantly improved their accuracy in both non-cancer and cancer populations.
Graphical abstract
•The effects of glucose-lowering drugs in patients with type 2 diabetes (T2D) are potentially mediated by gut microbiota, and these drugs may also directly influence microbiome composition.•It has ...not been ascertained whether either dapagliflozin or gliclazide influences microbiome composition in patients with T2D.•This study found that microbiome composition was not altered by either dapagliflozin or gliclazide treatment.•Thus, the metabolic effects of either treatment are not likely to be driven by changes in colonic microbiome composition.
Patients with type 2 diabetes (T2D) are usually treated with (combinations of) glucose-lowering medication. The effects of these drugs can be influenced by intestinal microbiota and vice versa, as these drugs can also influence microbiome composition. However, as there is currently little clinical insight into this bug–drug interaction, our study aimed to evaluate the effects of 12-week treatment with the SGLT2 inhibitor dapagliflozin and sulphonylurea gliclazide on gut microbiome composition in T2D patients treated with metformin.
A total of 44 patients were randomized to either dapagliflozin or gliclazide treatment for 12 weeks. At baseline and after 12 weeks, faecal samples and 24-h urine were collected. During study visits, anthropometric data were measured and blood samples drawn after an overnight fast. Microbiome composition was determined by 16S rRNA gene sequencing. Plasma glucose, insulin, HbA1c and urinary glucose excretion were measured using conventional methods.
While dapagliflozin and gliclazide similarly improved glycaemic control, dapagliflozin reduced and gliclazide increased fasting insulin. Dapagliflozin also greatly increased urinary glucose excretion whereas gliclazide did not, while body mass index, fat mass percentage and waist circumference were reduced by dapagliflozin, but increased by gliclazide. However, neither treatment significantly affected either gut microbiome alpha diversity or composition and, after treatment, no associations were found between microbiome composition and other clinical parameters.
Even though gliclazide and dapagliflozin have different metabolic actions in patients with T2D, neither treatment altered the faecal microbiome, thereby suggesting that the observed metabolic changes are not mediated by their effects on the microbiota.
Metal hydride materials offer attractive solutions in addressing problems associated with hydrogen separation and purification from waste flue gases. However, a challenging problem is the ...deterioration of hydrogen charging performances resulting from the surface chemical action of electrophilic gases. In this work, the feasibility study of poisoning tolerance of surface modified AB5-type hydride forming materials and their application for hydrogen separation from process gases containing carbon dioxide and monoxide was carried out. Target composition of La(Ni,Co,Mn,Al)5 substrate was chosen to provide maximum reversible hydrogen capacity at the process conditions. The selected substrate alloy has been shown to be effectively surface-modified by fluorination followed by electroless deposition of palladium. The surface-modified material exhibited good coating quality, high cycle stability and minimal deterioration of kinetics of selective hydrogen absorption at room temperature, from gas mixtures containing 10% CO2 and up to 100 ppm CO. The experimental prototype of a hydrogen separation unit, based on the surface-modified metal hydride material, was tested and exhibited stable hydrogen separation and purification performances when exposed to feedstocks containing concentrations of CO2 and CO of up to 30% and 100 ppm, respectively.
•Metal hydrides for H2 separation at PH2≥2.5bar/T≤80°C; H2 output at P ∼ 1 bar/T∼200 °C.•La(Ni,Co,Al,Mn)5 is suitable for the operation at the specified conditions.•Surface modification of the alloy adds tolerance to its poisoning by CO2 and CO.•Prototype H2 separation system (25%H2, ≤30%CO2, 100 ppm CO) successfully demonstrated.•Efficiency of N2 and CO2 removal about 90%.
Cancer stem cells: A product of clonal evolution? van Niekerk, Gustav; Davids, Lester M.; Hattingh, Suzèl M. ...
International journal of cancer,
1 March 2017, Letnik:
140, Številka:
5
Journal Article
Recenzirano
Odprti dostop
The cancer stem cell (CSC) model has emerged as a prominent paradigm for explaining tumour heterogeneity. CSCs in tumour recurrence and drug resistance have also been implicated in a number of ...studies. In fact, CSCs are often identified by their expression of drug‐efflux proteins which are also highly expressed in normal stem cells. Similarly, pro‐survival or proliferation signalling often exhibited by stem cells is regularly reported as being upregulated by CSC. Here we review evidence suggesting that many aspects of CSCs are more readily described by clonal evolution. As an example, cancer cells often exhibit copy number gains of genes involved in drug‐efflux proteins and pro‐survival signalling. Consequently, clonal selection for stem cell traits may result in cancer cells developing “stemness” traits which impart a fitness advantage, without strictly following a CSC model. Finally, since symmetric cell division would give rise to more cells than asymmetric division, it is expected that more advanced tumours would depart from a CSC. Collectively, these observations suggest clonal evolution may explain many aspects of the CSC.
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