Protein Folding Activity of the Ribosome (PFAR) –– A Target for Antiprion Compounds

Prion diseases are fatal neurodegenerative diseases affecting mammals. Prions are misfolded amyloid aggregates of the prion protein (PrP), which form when the alpha helical, soluble form of PrP converts to an aggregation-prone, beta sheet form. Thus, prions originate as protein folding problems. The discovery of yeast prion(s) and the development of a red-/white-colony based assay facilitated safe and high-throughput screening of antiprion compounds. With this assay three antiprion compounds; 6-aminophenanthridine (6AP), guanabenz acetate (GA), and imiquimod (IQ) have been identified. Biochemical and genetic studies reveal that these compounds target ribosomal RNA (rRNA) and inhibit specifically the protein folding activity of the ribosome (PFAR). The domain V of the 23S/25S/28S rRNA of the large ribosomal subunit constitutes the active site for PFAR. 6AP and GA inhibit PFAR by competition with the protein substrates for the common binding sites on the domain V rRNA. PFAR inhibition by these antiprion compounds opens up new possibilities for understanding prion formation, propagation and the role of the ribosome therein. In this review, we summarize and analyze the correlation between PFAR and prion processes using the antiprion compounds as tools.     

A Systematic Review of Palliative Care Intervention Outcomes and Outcome Measures in Low-Resource Countries

Context

To meet the growing need for palliative care in low-resource countries, palliative care programs should be evidence based and contextually appropriate. This study was conducted to synthesize the current evidence to guide future programmatic and research efforts.

Left Ventricular Dysfunction and Chemotherapeutic Agents

Purpose of Review

We aim to summarize the effect of cancer therapy-related cardiotoxicity on the development of left ventricular (LV) dysfunction.

Recent Findings

We discuss commonly used cancer therapeutics that have the potential for both acute and delayed cardiotoxicity. LV dysfunction from cancer therapies may be found by routine cardiac imaging prior to clinical manifestations of heart failure (HF) and we discuss the current multi-modality approaches for early detection of toxicity with the use of advanced echocardiographic parameters including strain techniques. Further, we discuss the role of biomarkers for detection of LV dysfunction from cancer therapies. Current approaches monitoring and treating LV dysfunction related to cancer therapy-related cardiotoxicity include addressing modifiable cardiovascular risk factors especially hypertension and early initiation of neurohormonal blockade (NHB) with disease-modifying beta-blockers and renin–angiotensin–aldosterone system (RAAS) inhibitors. Once LV dysfunction is identified, traditional ACC/AHA guideline-directed therapy is employed. Further, we highlight the use of advanced heart failure therapies including mechanical resynchronization devices, the use of durable ventricular assist devices, and cardiac transplantation as increasingly employed modalities for treatment of severe LV dysfunction and advanced heart failure in the cardio-oncology population.

Summary

This review seeks to highlight the importance of early detection, treatment, and prevention of LV dysfunction from cancer therapy-related cardiotoxicity.

     

Interactions between NKT cells and Tregs are required for tolerance to combined bone marrow and organ transplants

We used a model of combined bone marrow and heart transplantation, in which tolerance and stable chimerism is induced after conditioning with fractionated irradiation of the lymphoid tissues and anti-T-cell antibodies. Graft acceptance and chimerism required host CD4(+)CD25(+) Treg production of IL-10 that was in-turn enhanced by host invariant natural killer (NK) T-cell production of IL-4. Up-regulation of PD-1 on host Tregs, CD4(+)CD25(-) conventional T (Tcon) cells, and CD8(+) T cells was also enhanced by NKT cell production of IL-4. Up-regulated PD-1 expression on Tregs was linked to IL-10 secretion, on CD8(+) T cells was linked to Tim-3 expression, and on CD4(+) Tcon cells was associated with reduced IFNγ secretion. Changes in the expression of PD-1 were induced by the conditioning regimen, and declined after bone marrow transplantation. In conclusion, NKT cells in this model promoted changes in expression of negative costimulatory receptors and anti-inflammatory cytokines by Tregs and other T-cell subsets in an IL-4-dependent manner that resulted in tolerance to the bone marrow and organ grafts.     

Clinical effectiveness and safety of escitalopram and desvenlafaxine in patients of depression with anxiety: A randomized,open-label controlled trial

Aim:

Selective serotonin reuptake inhibitors (SSRI) and serotonin-norepinephrine reuptake inhibitors (SNRI) are effective in treating anxiety disorders associated with major depressive disorder (MDD). This randomized, controlled, parallel-group, open-label, phase 4 trial (CTRI/2012/08/002895) was undertaken to compare the effectiveness and safety of desvenlafaxine versus escitalopram, a standard antidepressant.

Materials and Methods:

Effectiveness was assessed using the Hamilton Depression Rating Scale (HAM-D₁₇) and Hamilton Anxiety Rating Scale (HAM-A). Response to treatment was assessed by ≥50% decrease of baseline scores (responder rate). Safety and tolerability was evaluated by changes in routine laboratory parameters, vital signs, and adverse events reported by the subject and/or observed by the clinician.

Results:

Responder rates for both HAM-A and HAM-D scores at 8 weeks were better in the escitalopram group compared to the desvenlafaxine group (HAM-A 76.92% vs. 71.05%; HAM-D 79.48% vs 73.68%) but the differences were not statistically significant (P = 0.59 and P = 0.61). Within group changes of both scores, from baseline to subsequent visits in both treatment arms were statistically significant (P < 0.01).

Conclusion:

The effectiveness of desvenlafaxine was comparable to escitalopram, but escitalopram was better tolerated.KEY WORDS: Anxiety, clinical trial, desvenlafaxine, escitalopram, major depressive disorder     

Proteasomal degradation of human peptidyl prolyl isomerase pin1-pointing phospho Bcl2 toward dephosphorylation

Microtubule inhibitor-induced Bcl2 phosphorylation is detrimental to its antiapoptotic function. Phosphorylation of Bcl2 predominantly occurs on two serine residues (70 and 87) in cells arrested at G2-M phase by microtubule disarraying agents. Phospho Bcl2 can associate with a cis-trans peptidyl prolyl isomerase, Pin1. Pin1 and its homologues are known to target the proline residue carboxyl terminal to the phosphorylated threonine or serine residue of mitotic phosphoproteins, such as Bcl2. However, it was not clear how an extranuclear protein could associate with nuclear Pin1. The confocal images of the immunofluorescence studies employing phospho Bcl2-specific antibody developed in the laboratory demonstrated the translocation of phospho Bcl2 inside the nucleus. Interestingly, proteasomal degradation of Pin1 facilitates dephosphorylation of phospho Bcl2 due to longer exposure of Taxol. Here we show for the first time that proteasomal degradation of Pin1 is the key factor to determine the fate of phosphoforms of Bcl2. When Pin1 is degraded by proteasomes, phospho Bcl2 is converted to its native form. Thus, transient conformational change of Bcl2 due to association with peptidyl prolyl isomerase can contribute to irreversible apoptotic signaling.     

Leptin levels are appropriate for body mass index in older men who experience involuntary weight loss

OBJECTIVES: To determine the relationship between leptin and unintentional weight loss in older adults. DESIGN: Prospective cohort study over 2 years. SETTING: University-affiliated Veterans Affairs Medical Center. PARTICIPANTS: The subjects were 105 community-dwelling male veterans aged 65 and older who had participated in a prospective cohort study on nutrition and health conducted at the Veterans Affairs Puget Sound Health Care System from 1986 to 1989. MEASUREMENTS: Anthropometric data and fasting blood specimens were collected at baseline and annually for the subsequent 2 years. Stored blood specimens were analyzed for leptin, insulin, glucose, C-reactive protein, sex hormone binding globulin, and testosterone levels. RESULTS: Over 2 years, 75 men were weight stable (weight loss <4% of baseline) and 30 men had unintentional weight loss (weight loss>4% of baseline). The baseline body mass index (BMI) and leptin levels for the two groups were not statistically different. Positive correlations existed between leptin level and BMI at each time point for weight-stable and weight-loss subjects. Furthermore, a significant relationship existed between changes in leptin and changes in BMI over 1 year in multiple regression analysis (r =.436, P <.001 after the first year; and r =.630, P =.027 after the second year). CONCLUSIONS: Like in younger adults, plasma leptin levels remained proportional to BMI, and changes in BMI were accurately reflected by changes in leptin levels in older individuals. Fasting leptin levels did not predict involuntary weight loss over 2 years of follow-up.     

Restoration of silenced Peutz-Jeghers syndrome gene, LKB1, induces apoptosis in pancreatic carcinoma cells

Germ line mutations of the LKB1 tumor suppressor gene lead to Peutz-Jeghers syndrome (PJS) with a predisposition to cancer. Previous reports suggest that inactivation of this tumor-suppressor gene plays a role in the pathogenesis of gastrointestinal hamartomas as well as several cancers, including adenocarcinoma of the pancreas. Here, we have shown that LKB1 gene is silenced in the pancreatic cancer cell line AsPC-1, but can be recovered by treatment with the methylation inhibitor, 5-aza-2'-deoxycytidine (5aza2dC). Restoring the level of LKB1 through gene transfer initiated mitochondria-mediated apoptosis in AsPC-1 cells, as evidenced by the release of cytochrome c from the mitochondria. By confocal microscopy as well as biochemical fractionation, we demonstrate that LKB1 is present in the nuclear and mitochondrial compartments of pancreatic cancer cells. Our observations also indicate that although functional p53 is absent, the p53 kin, p73, is inducible by doxorubicin in AsPC-1 cells. This suggests that LKB1-induced apoptosis is p53 independent but might be p73-mediated in the pancreatic tumor cell line, AsPC-1.     

Oral cancer screening: Practices, knowledge, and opinions of dentists working in Ohio nursing homes

The state of oral health of nursing homes residents is less than satisfactory. The oral health care in nursing homes is also deficient, therefore it is likely that oral cancer (OC) screening of residents will be inadequate. The purpose of this cross-sectional study was to determine OC screening practices, knowledge, and opinions of dentists working in nursing homes throughout Ohio. A 28-item pretested questionnaire was mailed to 75 dentists who were serving 606 nursing homes.
The response rate was 49%. The main outcome measures of interest included: OC screening practices of the Ohio dentists, their knowledge of OC detection, and their opinions regarding OC screening competency. Age was found to be a significant factor, with younger dentists being more likely to have higher knowledge scores after adjusting for all other covariates.