The Experiences of Caregivers Caring for Loved Ones with Dementia

The Alzheimer’s Association indicates there are almost 15 million caregivers providing care to those diagnosed with Alzheimer’s disease and dementia (2011). Oftentimes family members willingly assume the role of caregiver for their loved ones as dementia progresses and cognitive abilities begin to fail. As a result, this qualitative research sought to explore the experiences of caregivers caring for a loved one with dementia. Seven participants were asked open-ended questions designed to elicit responses that explained their experiences caring for a loved one with dementia. The research participants were the primary caregivers for their loved ones for whom they were either providing in-home care or were the primary contact for the facility where their loved one was residing. Research participants’ loved ones had a diagnosis of dementia of the Alzheimer’s type, frontotemporal dementia, or dementia - unknown, and participants were the primary caregiver caring for their loved one for a time period of two to five years. The findings indicated caregiving does contribute to relationship and life changes and has its challenges; however, it was found that caregiving can also be a rewarding experience and caregivers do continue to participate in self-care activities, despite their important responsibilities. It was also found that caregivers today are still in need of help and support from other family members and friends

The Experiences of Caregivers Caring for Loved Ones with Dementia

The Alzheimer’s Association indicates there are almost 15 million caregivers providing care to those diagnosed with Alzheimer’s disease and dementia (2011). Oftentimes family members willingly assume the role of caregiver for their loved ones as dementia progresses and cognitive abilities begin to fail. As a result, this qualitative research sought to explore the experiences of caregivers caring for a loved one with dementia. Seven participants were asked open-ended questions designed to elicit responses that explained their experiences caring for a loved one with dementia. The research participants were the primary caregivers for their loved ones for whom they were either providing in-home care or were the primary contact for the facility where their loved one was residing. Research participants’ loved ones had a diagnosis of dementia of the Alzheimer’s type, frontotemporal dementia, or dementia - unknown, and participants were the primary caregiver caring for their loved one for a time period of two to five years. The findings indicated caregiving does contribute to relationship and life changes and has its challenges; however, it was found that caregiving can also be a rewarding experience and caregivers do continue to participate in self-care activities, despite their important responsibilities. It was also found that caregivers today are still in need of help and support from other family members and friends

Clinicians’ Real World Perceptions of Pre-Nephrectomy Diagnostic Biopsy Performance as a Driver of Reduction in Unnecessary Surgeries in Renal Tumors

Operative removal of oncocytomas is generally unnecessary, but not infrequent in the context of renal masses. The infrequent use of pre-nephrectomy biopsies is a function of historical limitations of histopathological differential diagnosis in this setting. Assessment of clinicians’ receptiveness to a novel molecular diagnostic approach to this challenge was undertaken by means of a survey vehicle administered to 102 practicing urologists and pathologists who met inclusion criteria related to their actual clinical activity. Survey results supported the previously reported observations on misdiagnosis with urologists’ reported rates of 25% inconclusive results, and an additional 17% disagree with the final surgical diagnosis. The self-reported rate of 9% for pre-operative biopsies was comparable to prior reports, but 39% of urologists who are not currently performing pre-operative biopsies expressed interest in introducing them into their practice for this purpose with an improved diagnostic. Almost all urologists (94%) felt it important not to resect benign oncocytomas and 62% indicated they would use a test which improved the ability to sub-type renal tumors pre-operatively. The level of performance benchmark of the unidentified prototypic microRNA-based diagnostic as reported previously in the literature was deemed sufficient to change care in these cases by 73%. Overall they predicted a 38% rate of biopsies and resulting increases in decisions to forgo nephrectomy or to perform only partial nephrectomy. Pathologists also expressed support for the use of this technology in the context of inadequate specimens and for improved sub-typing of these tumors in inconclusive cases. Supplementary files: The supplementary files of this article are found under 'Article Tools' at the left side bar

Exploiting transient protein states for the design of small-molecule stabilizers of mutant p53

The destabilizing p53 cancer mutation Y220C creates an extended crevice on the surface of the protein that can be targeted by small-molecule stabilizers. Here, we identify different classes of small molecules that bind to this crevice and determine their binding modes by X-ray crystallography. These structures reveal two major conformational states of the pocket and a cryptic, transiently open hydrophobic subpocket that is modulated by Cys220. In one instance, specifically targeting this transient protein state by a pyrrole moiety resulted in a 40-fold increase in binding affinity. Molecular dynamics simulations showed that both open and closed states of this subsite were populated at comparable frequencies along the trajectories. Our data extend the framework for the design of high-affinity Y220C mutant binders for use in personalized anticancer therapy and, more generally, highlight the importance of implementing protein dynamics and hydration patterns in the drug-discovery process

Nitroimidazole Action in Entamoeba histolytica: A Central Role for Thioredoxin Reductase

Metronidazole, a 5-nitroimidazole drug, has been the gold standard for several decades in the treatment of infections with microaerophilic protist parasites, including Entamoeba histolytica. For activation, the drug must be chemically reduced, but little is known about the targets of the active metabolites. Applying two-dimensional gel electrophoresis and mass spectrometry, we searched for protein targets in E. histolytica. Of all proteins visualized, only five were found to form adducts with metronidazole metabolites: thioredoxin, thioredoxin reductase, superoxide dismutase, purine nucleoside phosphorylase, and a previously unknown protein. Recombinant thioredoxin reductase carrying the modification displayed reduced enzymatic activity. In treated cells, essential non-protein thiols such as free cysteine were also affected by covalent adduct formation, their levels being drastically reduced. Accordingly, addition of cysteine allowed E. histolytica to survive in the presence of otherwise lethal metronidazole concentrations and reduced protein adduct formation. Finally, we discovered that thioredoxin reductase reduces metronidazole and other nitro compounds, suggesting a new model of metronidazole activation in E. histolytica with a central role for thioredoxin reductase. By reducing metronidazole, the enzyme renders itself and associated thiol-containing proteins vulnerable to adduct formation. Because thioredoxin reductase is a ubiquitous enzyme, similar processes could occur in other eukaryotic or prokaryotic organisms

Ensemble-Based Computational Approach Discriminates Functional Activity of p53 Cancer and Rescue Mutants

The tumor suppressor protein p53 can lose its function upon single-point missense mutations in the core DNA-binding domain (“cancer mutants”). Activity can be restored by second-site suppressor mutations (“rescue mutants”). This paper relates the functional activity of p53 cancer and rescue mutants to their overall molecular dynamics (MD), without focusing on local structural details. A novel global measure of protein flexibility for the p53 core DNA-binding domain, the number of clusters at a certain RMSD cutoff, was computed by clustering over 0.7 µs of explicitly solvated all-atom MD simulations. For wild-type p53 and a sample of p53 cancer or rescue mutants, the number of clusters was a good predictor of in vivo p53 functional activity in cell-based assays. This number-of-clusters (NOC) metric was strongly correlated (r2 = 0.77) with reported values of experimentally measured ΔΔG protein thermodynamic stability. Interpreting the number of clusters as a measure of protein flexibility: (i) p53 cancer mutants were more flexible than wild-type protein, (ii) second-site rescue mutations decreased the flexibility of cancer mutants, and (iii) negative controls of non-rescue second-site mutants did not. This new method reflects the overall stability of the p53 core domain and can discriminate which second-site mutations restore activity to p53 cancer mutants

Small molecule compounds targeting the p53 pathway: are we finally making progress?

Loss of function of p53, either through mutations in the gene or through mutations to other members of the pathway that inactivate wild-type p53, remains a critically important aspect of human cancer development. As such, p53 remains the most commonly mutated gene in human cancer. For these reasons, pharmacologic activation of the p53 pathway has been a highly sought after, yet unachieved goal in developmental therapeutics. Recently progress has been made not only in the discovery of small molecules that target wild-type and mutant p53, but also in the initiation and completion of the first in-human clinical trials for several of these drugs. Here, we review the current literature of drugs that target wild-type and mutant p53 with a focus on small-molecule type compounds. We discuss common means of drug discovery and group them according to their common mechanisms of action. Lastly, we review the current status of the various drugs in the development process and identify newer areas of p53 tumor biology that may prove therapeutically useful