Prospective identification of patients with chronic lymphocytic leukemia (CLL) destined to progress would greatly facilitate their clinical management. Recently, whole-genome DNA methylation analyses ...identified three clinicobiologic CLL subgroups with an epigenetic signature related to different normal B-cell counterparts. Here, we developed a clinically applicable method to identify these subgroups and to study their clinical relevance. Using a support vector machine approach, we built a prediction model using five epigenetic biomarkers that was able to classify CLL patients accurately into the three subgroups, namely naive B-cell-like, intermediate and memory B-cell-like CLL. DNA methylation was quantified by highly reproducible bisulfite pyrosequencing assays in two independent CLL series. In the initial series (n=211), the three subgroups showed differential levels of IGHV (immunoglobulin heavy-chain locus) mutation (P<0.001) and VH usage (P<0.03), as well as different clinical features and outcome in terms of time to first treatment (TTT) and overall survival (P<0.001). A multivariate Cox model showed that epigenetic classification was the strongest predictor of TTT (P<0.001) along with Binet stage (P<0.001). These findings were corroborated in a validation series (n=97). In this study, we developed a simple and robust method using epigenetic biomarkers to categorize CLLs into three subgroups with different clinicobiologic features and outcome.
ABSTRACTBackground:This systematic overview reports findings from systematic reviews of randomized controlled trials of pharmacological and non-pharmacological interventions for behavioural and ...psychological symptoms of dementia (BPSD).
The Cochrane Database of Systematic Reviews, DARE, Medline, EMBASE, and PsycINFO were searched to September 2015.
Fifteen systematic reviews of eighteen different interventions were included. A significant improvement in BPSD was seen with: functional analysis-based interventions (GRADE quality of evidence moderate; standardized mean difference (SMD) -0.10, 95%CI -0.20 to 0.00), music therapy (low; SMD -0.49, 95%CI -0.82 to -0.17), analgesics (low; SMD -0.24, 95%CI -0.47 to -0.01), donepezil (high; SMD -0.15 95% CI -0.29 to -0.01), galantamine (high; SMD -0.15, 95%CI -0.28 to -0.03), and antipsychotics (high; SMD -0.13, 95%CI -0.21 to -0.06). The estimate of effect size for most interventions was small.
Although some pharmacological interventions had a slightly larger effect size, current evidence suggests functional analysis-based interventions should be used as first line management of BPSD whenever possible due to the lack of associated adverse events. Music therapy may also be beneficial, but further research is required as the quality of evidence to support its use is low. Cholinesterase inhibitors donepezil and galantamine should be trialled for the management of BPSD where non-pharmacological treatments have failed. Low-quality evidence suggests that assessment of pain should be conducted and a stepped analgesic approach trialled when appropriate. Antipsychotics have proven effectiveness but should be avoided where possible due to the high risk of serious adverse events and availability of safer alternatives.
Despite tremendous advances over the last 15 years in understanding fundamental mechanisms of apoptosis, this has failed to translate into improved cancer therapy for patients. However, there may now ...be light at the end of this long tunnel. Antiapoptotic Bcl-2 family members may be divided into two subclasses, one comprising Bcl-2, Bcl-X(L) and Bcl-w and the other Mcl-1 and Bcl2A1. Neutralization of both subclasses is required for apoptosis induction. Solution of the structure of antiapoptotic Bcl-2 family proteins has led to the design of novel small molecule inhibitors. Although many such molecules have been synthesized, rigorous verification of their specificity has often been lacking. Further studies have revealed that many putative Bcl-2 inhibitors are not specific and have other cellular targets, resulting in non-mechanism based toxicity. Two notable exceptions are ABT-737 and a related orally active derivative, ABT-263, which bind with high affinity to Bcl-2, Bcl-X(L) and Bcl-w and may prove to be useful tools for mechanistic studies. ABT-263 is in early clinical trials in lymphoid malignancies, small-cell lung cancer and chronic lymphocytic leukemia, and some patients have shown promising results. In in vitro studies, primary cells from patients with various B-cell malignancies are exquisitely sensitive to ABT-737, exhibiting novel morphological features of apoptosis including marked outer mitochondrial membrane rupture.
Hip fractures are an increasingly common consequence of falls in older people that are associated with a high risk of death and reduced function. This review aims to quantify the impact of hip ...fracture on older people's abilities and quality of life over the long term.
Studies were identified through PubMed and Scopus searches and contact with experts. Cohort studies of hip fracture patients reporting outcomes 3 months post-fracture or longer were included for review. Outcomes of mobility, participation in domestic and community activities, health, accommodation or quality of life were categorised according to the World Health Organization's International Classification of Functioning and synthesised narratively. Risk of bias was assessed according to four items from the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement.
Thirty-eight studies from 42 publications were included for review. Most followed a clearly defined sample from the time of fracture. Hip fracture survivors experienced significantly worse mobility, independence in function, health, quality of life and higher rates of institutionalisation than age matched controls. The bulk of recovery of walking ability and activities for daily living occurred within 6 months after fracture. Between 40 and 60 % of study participants recovered their pre-fracture level of mobility and ability to perform instrumental activities of daily living, while 40-70 % regained their level of independence for basic activities of daily living. For people independent in self-care pre-fracture, 20-60 % required assistance for various tasks 1 and 2 years after fracture. Fewer people living in residential care recovered their level of function than those living in the community. In Western nations, 10-20 % of hip fracture patients are institutionalised following fracture. Few studies reported impact on participation in domestic, community, social and civic life.
Hip fracture has a substantial impact on older peoples' medium- to longer-term abilities, function, quality of life and accommodation. These studies indicate the range of current outcomes rather than potential improvements with different interventional approaches. Future studies should measure impact on life participation and determine the proportion of people that regain their pre-fracture level of functioning to investigate strategies for improving these important outcomes.
Summary Acute compartment syndrome of the extremities is well known, but diagnosis can be challenging. Ineffective treatment can have devastating consequences, such as permanent dysaesthesia, ...ischaemic contractures, muscle dysfunction, loss of limb, and even loss of life. Despite many studies, there is no consensus about the way in which acute extremity compartment syndromes should be diagnosed. Many surgeons suggest continuous monitoring of intracompartmental pressure for all patients who have high-risk extremity injuries, whereas others suggest aggressive surgical intervention if acute compartment syndrome is even suspected. Although surgical fasciotomy might reduce intracompartmental pressure, this procedure also carries the risk of long-term complications. In this paper in The Lancet Series about emergency surgery we summarise the available data on acute extremity compartment syndrome of the upper and lower extremities in adults and children, discuss the underlying pathophysiology, and propose a clinical guideline based on the available data.
Plant oils represent an energy-rich and carbon-dense group of hydrophobic compounds. These oils are not only of economic interest, but also play important, fundamental roles in plant and algal growth ...and development. The subcellular storage compartments of plant lipids, referred to as lipid droplets (LDs), have long been considered relatively inert oil vessels. However, research in the last decade has revealed that LDs play far more dynamic roles in plant biology than previously appreciated, including transient neutral lipid storage, membrane remodeling, lipid signaling, and stress responses. Here we discuss recent developments in the understanding of LD formation, turnover and function in land plants and algae.
Mechanisms of lipid droplet biogenesis Chapman, Kent D; Aziz, Mina; Dyer, John M ...
Biochemical journal,
07/2019, Volume:
476, Issue:
13
Journal Article
Peer reviewed
Lipid droplets (LDs) are organelles that compartmentalize nonbilayer-forming lipids in the aqueous cytoplasm of cells. They are ubiquitous in most organisms, including in animals, protists, plants ...and microorganisms. In eukaryotes, LDs are believed to be derived by a budding and scission process from the surface of the endoplasmic reticulum, and this occurs concomitantly with the accumulation of neutral lipids, most often triacylglycerols and steryl esters. Overall, the mechanisms underlying LD biogenesis are difficult to generalize, in part because of the involvement of different sets of both evolutionarily conserved and organism-specific LD-packaging proteins. Here, we briefly compare and contrast these proteins and the allied processes responsible for LD biogenesis in cells of animals, yeasts and plants.
Cooking‐Induced Protein Modifications in Meat Yu, Tzer‐Yang; Morton, James D.; Clerens, Stefan ...
Comprehensive reviews in food science and food safety,
January 2017, Volume:
16, Issue:
1
Journal Article
Peer reviewed
Open access
Food ingredients commonly undergo heat treatment. Meat, in particular, is typically consumed after some form of heating, such as boiling or roasting. Heating of meat can introduce a wide range of ...structural changes in its proteinaceous components. At the 3‐dimensional structural level, meat proteins may denature and form aggregates upon heating. At the molecular level, primary structure (amino acid residue) alterations reported in cooked meat include protein carbonylation, modification of aromatic residues, and the formation of Maillard reaction products. Identification of these modifications is essential for determining the mechanism of thermal processing of meat and allowing better control of the nutritional and functional properties of products. This article reviews and summarizes the current state of understanding of protein modifications at the molecular level in commonly consumed mammalian food. In addition, relevant case studies relating to characterization of heat‐induced amino acid residue‐level modifications in other biological materials such as milk and wool are discussed to provide complementary insights.
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