Recent clinical successes with immunotherapy have resulted in expanding indications for cancer therapy. To enhance antitumor immune responses, and to better choose specific strategies matched to ...patient and tumor characteristics, genomic-driven precision immunotherapy will be necessary. Herein, we explore the role that tumor gene-expression profiling (GEP) may have in the prediction of an immunotherapeutic response. Genetic markers associated with response to immunotherapy are addressed as they pertain to the tumor genomic landscape, the extent of DNA damage, tumor mutational load and tumor-specific neoantigens. Furthermore, genetic markers associated with resistance to checkpoint blockade and relapse are reviewed. Finally, the utility of GEP to identify new tumor types for immunotherapy and implications for combinatorial strategies are summarized.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Oxytocin (OT) is a neuropeptide that exerts multiple actions throughout the brain and periphery. Within the brain, OT regulates diverse neural populations, including neural networks controlling ...responses to stress. Local release of OT within the paraventricular nucleus (PVN) of the hypothalamus has been suggested to regulate stress responses by modulating the excitability of neighbouring corticotropin‐releasing hormone (CRH) neurones. However, the mechanisms by which OT regulates CRH neurone excitability are unclear. In the present study, we investigated the morphological relationship between OT and CRH neurones and determined the effects of OT on CRH neurone excitability. Morphological analysis revealed that the processes of OT and CRH neurones were highly intermingled within the PVN, possibly allowing for local cell‐to‐cell cross‐talk. Whole‐cell patch‐clamp recordings from CRH neurones were used to study the impact of OT on postsynaptic excitability and synaptic innervation. Bath‐applied OT did not alter CRH neurone holding current, spiking output or any action potential parameters. Recordings of evoked excitatory and inhibitory postsynaptic currents (EPSCs/IPSCs) revealed no net effect of OT on current amplitude; however, subgroups of CRH neurones appeared to respond differentially to OT. Analysis of spontaneous EPSC events uncovered a significant reduction in spontaneous EPSC frequency but no change in spontaneous EPSC amplitude in response to OT. Together, these data demonstrate that OT exerts a subtle modulation of synaptic transmission onto CRH neurones providing one potential mechanism by which OT could suppress CRH neurone excitability and stress axis activity.
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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
Alzheimer's disease (AD), the most prevalent, age-related, neurodegenerative disease, is associated with the accumulation of amyloid beta (Aβ) and oxidative stress. However, the sporadic nature of ...late-onset AD has suggested that other factors, such as aluminium may be involved. Aluminium (Al
) is the most ubiquitous neurotoxic metal on earth, extensively bioavailable to humans. Despite this, the link between Al
and AD has been debated for decades and remains controversial. Using
as a model organism expressing Aβ42, this study aimed to examine the mechanisms of Al
toxicity and its interactions with Aβ42.
cells producing Aβ42 treated with varying concentrations of Al
were examined for cell viability, growth inhibition, and production of reactive oxygen species (ROS). Al
caused a significant reduction in cell viability: cell death in yeast producing green fluorescent protein tagged with Aβ42 (GFP-Aβ42) was significantly higher than in cells producing green fluorescent protein (GFP) alone. Additionally, Al
greatly inhibited the fermentative growth of yeast producing GFP-Aβ42, which was enhanced by ferric iron (Fe
), while there was negligible growth inhibition of GFP cells. Al
- induced ROS levels in yeast expressing native Aβ42 were significantly higher than in empty vector controls. These findings demonstrate Al
has a direct, detrimental toxic synergy with Aβ42 that can be influenced by Fe
, causing increased oxidative stress. Thus, Al
should be considered as an important factor, alongside the known characteristic hallmarks of AD, in the development and aetiology of the disease.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
We measured the prevalence and temporal trends of pulmonary nontuberculous mycobacterial disease among residents of Ontario, Canada, during 1998-2010. Five-year prevalence increased from 29.3 ...cases/100,000 persons in 1998-2002 to 41.3/100,000 in 2006-2010 (p<0.0001). Improved laboratory methods did not explain this increase, suggesting a surge in disease prevalence.
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DOBA, IZUM, KILJ, NUK, ODKLJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background
Pancreatic ductal adenocarcinoma (PDAC) remains a dismal disease, with very little improvement in survival over the past 50 years. Recent large‐scale genomic studies have improved ...understanding of the genomic and transcriptomic landscape of the disease, yet very little is known about molecular heterogeneity according to tumour location in the pancreas; body and tail PDACs especially tend to have a significantly worse prognosis. The aim was to investigate the molecular differences between PDAC of the head and those of the body and tail of the pancreas.
Methods
Detailed correlative analysis of clinicopathological variables, including tumour location, genomic and transcriptomic data, was performed using the Australian Pancreatic Cancer Genome Initiative (APGI) cohort, part of the International Cancer Genome Consortium study.
Results
Clinicopathological data were available for 518 patients recruited to the APGI, of whom 421 underwent genomic analyses; 179 of these patients underwent whole‐genome and 96 RNA sequencing. Patients with tumours of the body and tail had significantly worse survival than those with pancreatic head tumours (12·1 versus 22·0 months; P = 0·001). Location in the body and tail was associated with the squamous subtype of PDAC. Body and tail PDACs enriched for gene programmes involved in tumour invasion and epithelial‐to‐mesenchymal transition, as well as features of poor antitumour immune response. Whether this is due to a molecular predisposition from the outset, or reflects a later time point on the tumour molecular clock, requires further investigation using well designed prospective studies in pancreatic cancer.
Conclusion
PDACs of the body and tail demonstrate aggressive tumour biology that may explain worse clinical outcomes.
Worse genetic profile in tail
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Here we show that Rab25 permits the sorting of ligand-occupied, active-conformation α5β1 integrin to late endosomes/lysosomes. Photoactivation and biochemical approaches show that lysosomally ...targeted integrins are not degraded but are retrogradely transported and recycled to the plasma membrane at the back of invading cells. This requires CLIC3, a protein upregulated in Rab25-expressing cells and tumors, which colocalizes with active α5β1 in late endosomes/lysosomes. CLIC3 is necessary for release of the cell rear during migration on 3D matrices and is required for invasion and maintenance of active Src signaling in organotypic microenvironments. CLIC3 expression predicts lymph node metastasis and poor prognosis in operable cases of pancreatic ductal adenocarcinoma (PDAC). The identification of CLIC3 as a regulator of a recycling pathway and as an independent prognostic indicator in PDAC highlights the importance of active integrin trafficking as a potential drive to cancer progression in vivo.
► Activated integrins move from late endosomes/lysosomes to the plasma membrane ► Spatial segregation of pathways recycling active and inactive integrins ► CLIC3 regulates cell migration and invasion ► CLIC3 dictates whether Rab25 functions as cancer progression suppressor or promoter
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Objectives
Type 3c diabetes mellitus (T3cDM) occurring post pancreatectomy can be challenging to treat due to the frequent combination of decreased circulating levels of insulin and glucagon and ...concurrent exocrine insufficiency. Relatively, little is known regarding the risk factors for development of T3cDM post pancreatectomy. Our aim was to review the literature and assess what is known of the risk factors for the development of new‐onset DM following partial pancreatic resection and where possible determines the incidence, time of onset and the management approach to hyperglycaemia in this context.
Design
Medline and Embase databases were reviewed using specific keyword criteria. Original manuscripts published in 1990 or later included. Articles with study population <20, lacking information on new‐onset DM, follow‐up duration or specifically targeting rare procedures/pathology were excluded. The Newcastle Ottawa Quality Assessment form was applied. Results reported according to PRISMA guidelines. Pooled effect size calculated using random effects model.
Patients
Thirty six articles were identified that described a total of 5636 patients undergoing pancreaticoduodenectomy, 3922 patients having distal pancreatectomy and 315 with central pancreatectomy.
Results
The incidence of new‐onset DM was significantly different between different types of resection from 9% to 24% after pancreaticoduodenectomy (pooled estimate 16%; 95% CI: 14%‐17%), 3%‐40% after distal pancreatectomy (pooled estimate 21%; 95% CI: 16%‐25%) and 0%‐14% after central pancreatectomy (pooled estimate 6%; 95% CI: 3%‐9%). Surgical site, higher preoperative HbA1c, fasting plasma glucose and lower remnant pancreatic volume had strongest associations with new‐onset DM.
Conclusions
This systematic review supports that risk of development of T3cDM is associated with type of pancreatic resection, lower remnant pancreatic volume and higher preoperative HbA1c.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
In Ontario, Canada, during 1998-2010, nontuberculous mycobacteria (NTM) from pulmonary sites comprised 96% of species/patient combinations isolated; annual rates of isolation and cases increased ...steadily. NTM isolates from nonpulmonary sites comprised 4% of species/patient combinations; annual rates and cases were temporally stable. NTM increases were driven exclusively by pulmonary isolates and disease.
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DOBA, IZUM, KILJ, NUK, ODKLJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Integrin trafficking is key to cell migration, but little is known about the spatiotemporal organization of integrin endocytosis. Here, we show that α5β1 integrin undergoes tensin-dependent ...centripetal movement from the cell periphery to populate adhesions located under the nucleus. From here, ligand-engaged α5β1 integrins are internalized under control of the Arf subfamily GTPase, Arf4, and are trafficked to nearby late endosomes/lysosomes. Suppression of centripetal movement or Arf4-dependent endocytosis disrupts flow of ligand-bound integrins to late endosomes/lysosomes and their degradation within this compartment. Arf4-dependent integrin internalization is required for proper lysosome positioning and for recruitment and activation of mTOR at this cellular subcompartment. Furthermore, nutrient depletion promotes subnuclear accumulation and endocytosis of ligand-engaged α5β1 integrins via inhibition of mTORC1. This two-way regulatory interaction between mTORC1 and integrin trafficking in combination with data describing a role for tensin in invasive cell migration indicate interesting links between nutrient signaling and metastasis.
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•Tensin positions integrins for Arf4-dependent endocytosis•Photoactivation-in-TIRF microscopy pinpoints the site for integrin endocytosis•Integrin endocytosis dictates recruitment of mTORC1 to nearby late endosomes•Proinvasive trafficking pathway is regulated by nutrient status
Rainero et al. find that α5β1 integrins are first moved from the cell periphery to a region beneath the nucleus and from here are endocytosed and trafficked to late endosomes to support mTOR signaling. Control of this proinvasive pathway by nutrient status provides evidence for mechanistic links among ECM internalization, nutrient signaling, and metastasis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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