Glioblastoma (GBM) is a cancer comprised of morphologically, genetically, and phenotypically diverse cells. However, an understanding of the functional significance of intratumoral heterogeneity is ...lacking. We devised a method to isolate and functionally profile tumorigenic clones from patient glioblastoma samples. Individual clones demonstrated unique proliferation and differentiation abilities. Importantly, naüïve patient tumors included clones that were temozolomide resistant, indicating that resistance to conventional GBM therapy can preexist in untreated tumors at a clonal level. Further, candidate therapies for resistant clones were detected with clone-specific drug screening. Genomic analyses revealed genes and pathways that associate with specific functional behavior of single clones. Our results suggest that functional clonal profiling used to identify tumorigenic and drug-resistant tumor clones will lead to the discovery of new GBM clone-specific treatment strategies.
Significance Glioblastoma is an incurable brain tumor. It is characterized by intratumoral phenotypic and genetic heterogeneity, but the functional significance of this heterogeneity is unclear. We devised an integrated functional and genomic strategy to obtain single cell-derived tumor clones directly from patient tumors to identify mechanisms of aggressive clone behavior and drug resistance. Genomic analysis of single clones identified genes associated with clonal phenotypes. We predict that integration of functional and genomic analysis at a clonal level will be essential for understanding evolution and therapeutic resistance of human cancer, and will lead to the discovery of novel driver mechanisms and clone-specific cancer treatment.
Glioblastomas (GBM) grow in a rich neurochemical milieu, but the impact of neurochemicals on GBM growth is largely unexplored. We interrogated 680 neurochemical compounds in patient-derived GBM ...neural stem cells (GNS) to determine the effects on proliferation and survival. Compounds that modulate dopaminergic, serotonergic, and cholinergic signaling pathways selectively affected GNS growth. In particular, dopamine receptor D4 (DRD4) antagonists selectively inhibited GNS growth and promoted differentiation of normal neural stem cells. DRD4 antagonists inhibited the downstream effectors PDGFRβ, ERK1/2, and mTOR and disrupted the autophagy-lysosomal pathway, leading to accumulation of autophagic vacuoles followed by G0/G1 arrest and apoptosis. These results demonstrate a role for neurochemical pathways in governing GBM stem cell proliferation and suggest therapeutic approaches for GBM.
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•Dopaminergic, serotonergic, and cholinergic pathways affect GNS survival•GBM tumors and patient-derived GNS express functional DRD4 receptor•DRD4 antagonism selectively targets GNS growth in vitro and in vivo•GNS are vulnerable to DRD4-mediated disruption of autophagy-lysosomal pathway
Dolma et al. show that compounds that modulate dopaminergic, serotonergic, and cholinergic signaling pathways selectively affected glioblastoma neural stem cells (GNS). In particular, dopamine receptor D4 antagonists disrupt the autophagy-lysosomal pathway of GNS, leading to growth arrest and apoptosis.
Glioblastomas exhibit a hierarchical cellular organization, suggesting that they are driven by neoplastic stem cells that retain partial yet abnormal differentiation potential. Here, we show that a ...large subset of patient-derived glioblastoma stem cells (GSCs) express high levels of Achaete-scute homolog 1 (ASCL1), a proneural transcription factor involved in normal neurogenesis. ASCL1hi GSCs exhibit a latent capacity for terminal neuronal differentiation in response to inhibition of Notch signaling, whereas ASCL1lo GSCs do not. Increasing ASCL1 levels in ASCL1lo GSCs restores neuronal lineage potential, promotes terminal differentiation, and attenuates tumorigenicity. ASCL1 mediates these effects by functioning as a pioneer factor at closed chromatin, opening new sites to activate a neurogenic gene expression program. Directing GSCs toward terminal differentiation may provide therapeutic applications for a subset of GBM patients and strongly supports efforts to restore differentiation potential in GBM and other cancers.
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•GSCs can be classified into two subgroups based on ASCL1 expression•ASCL1 is required for GSCs to undergo neuronal lineage differentiation•ASCL1hi GSCs are responsive to Notch pathway inhibitors•ASCL1 binds closed chromatin to activate target genes that drive neuronal fate
Glioblastoma is characterized by a block in cellular differentiation. Park et al. identify a subset of glioblastoma stem cells (GSCs) that express high levels of the proneural transcription factor ASCL1 and differentiate in response to Notch inhibition, effectively abrogating their stemness properties and tumorigenic potential.
Fatigue and burnout are prevalent among resident physicians across Canada. Shifts exceeding 24 hours are commonly purported as detrimental to resident health and performance. Residency training ...programs have employed strategies towards understanding and intervening upon the complex issue of resident fatigue, where alternative resident scheduling models have been an area of active investigation. This study sought to characterize drivers and outcomes of fatigue and burnout amongst internal medicine residents across different scheduling models. We conducted cross-sectional surveys were among internal medicine resident physicians at the University of Alberta. We collected anonymized socioeconomic demographics and medical education background, and estimated associations between demographic or work characteristics and fatigue and burnout outcomes. Sixty-nine participants competed burnout questionnaires, and 165 fatigue questionnaires were completed (response rate of 48%). The overall prevalence of burnout was 58%. Lower burnout prevalence was noted among respondents with dependent(s) (p = 0.048), who identified as a racial minority (p = 0.018), or completed their medical degree internationally (p = 0.006). The 1-in-4 model was associated with the highest levels of fatigue, reported increased risk towards personal health (OR 4.98, 95%CI 1.77-13.99) and occupational or household harm (OR 5.69, 95%CI 1.87-17.3). Alternative scheduling models were not associated with these hazards. The 1-in-4 scheduling model was associated with high rates of resident physician fatigue, and alternative scheduling models were associated with less fatigue. Protective factors against fatigue are best characterized as strong social supports outside the workplace. Further studies are needed to characterize the impacts of alternative scheduling models on resident education and patient safety.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Pancreatic ductal adenocarcinoma (PDAC) is the most common malignancy of the pancreas and is associated with an extremely poor prognosis. Many PDAC patients suffer from profound nutritional ...complications such as nutrient deficiencies, weight loss, malnutrition, and cancer cachexia. These complications cause barriers to effective anticancer treatments, gravely influence their quality of life, and decrease their overall survival. Pancreatic exocrine insufficiency (PEI) is defined as impaired digestion due to inadequate secretion of pancreatic enzymes and is a common cause of malnutrition in PDAC. This review first summarizes the existing literature around malnutrition in PDAC, with a particular focus on PEI and its management with pancreatic enzyme replacement therapy (PERT). Second, we summarize existing guidelines and recommendations for the management of PEI among patients with PDAC. Lastly, we highlight potential gaps of knowledge of PEI among healthcare providers resulting in underdiagnosis and treatment, which may have implications for the quality of life and overall survival of PDAC patients.
Obesity is a major burden for modern medicine, with many links to negative health outcomes, including the increased incidence of certain cancer types. Interestingly, some studies have supported the ...concept of an “Obesity Paradox”, where some cancer patients living with obesity have been shown to have a better prognosis than non-obese patients. Neuroendocrine neoplasms (NENs) are malignancies originating from neuroendocrine cells, in some cases retaining important functional properties with consequences for metabolism and nutritional status. In this review, we summarize the existing evidence demonstrating that obesity is both a risk factor for developing NENs as well as a good prognostic factor. We further identify the limitations of existing studies and further avenues of research that will be necessary to optimize the metabolic and nutritional status of patients living with NENs to ensure improved outcomes.
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that leads to respiratory failure, and eventually death. However, there is a lack of effective treatments for ALS. Here ...we report the results of fecal microbiota transplantation (FMT) in two patients with late-onset classic ALS with a Japan ALS severity classification of grade 5 who required tracheostomy and mechanical ventilation. In both patients, significant improvements in respiratory function were observed following two rounds of FMT, leading to weaning off mechanical ventilation. Their muscle strength improved, allowing for assisted standing and mobility. Other notable treatment responses included improved swallowing function and reduced muscle fasciculations. Metagenomic and metabolomic analysis revealed an increase in beneficial
species (
,
,
), and
after FMT, as well as elevated levels of metabolites involved in arginine biosynthesis and decreased levels of metabolites involved in branched-chain amino acid biosynthesis. These findings offer a potential rescue therapy for ALS with respiratory failure and provide new insights into ALS in general.
Mutations in the histone 3 variant H3.3 have been identified in one-third of pediatric glioblastomas (GBMs), but not in adult tumors. Here we show that H3.3 is a dynamic determinant of functional ...properties in adult GBM. H3.3 is repressed by mixed lineage leukemia 5 (MLL5) in self-renewing GBM cells. MLL5 is a global epigenetic repressor that orchestrates reorganization of chromatin structure by punctuating chromosomes with foci of compacted chromatin, favoring tumorigenic and self-renewing properties. Conversely, H3.3 antagonizes self-renewal and promotes differentiation. We exploited these epigenetic states to rationally identify two small molecules that effectively curb cancer stem cell properties in a preclinical model. Our work uncovers a role for MLL5 and H3.3 in maintaining self-renewal hierarchies in adult GBM.
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•DNA methylomes of adult GBM self-renewing cells resemble H3.3-mutated pediatric GBM•MLL5 represses H3.3 levels in adult GBM self-renewing cells•MLL5 favors self-renewal and H3.3 favors differentiation in adult GBM•An MLL5/H3.3 signature predicted two compounds that curb GBM self-renewal
Gallo et al. show that MLL5 induces reorganization of chromatin structure and decreases expression of H3.3. Reduced H3.3 expression favors self-renewal properties of adult glioblastoma (GBM) cells and phenocopies pediatric GBM with H3.3 mutations, indicating potential therapeutic strategies for adult GBM.
Background:
There is a strong need for short and effective methods to screen for cognitive impairment. Recent studies have created short forms of the Montreal Cognitive Assessment (s-MoCA) in ...English-speaking populations. It is also important to develop a validated Chinese short version to detect cognitive impairment.
Methods:
Item response theory and computerized adaptive testing analytics were used to construct abbreviated MoCAs across a large neurological sample comprising 6,981 community-dwelling Chinese veterans.
Results:
Six MoCA items with high discrimination and appropriate difficulty were included in the s-MoCA. The Chinese short versions (sensitivity 0.89/0.90, specificity 0.72/0.77) are similar in performance to the full MoCA in identifying cognitive impairment (sensitivity 0.91, specificity 0.82).
Conclusions:
These short variants of the MoCA may serve as quick and effective instruments when the original MoCA cannot be feasibly administered in clinical services with a high patient burden and limited cognitive testing resources.
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