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1.  Cognitive Effects of Hormone Therapy in Men With Prostate Cancer 
Cancer  2008;113(5):1097-1106.
Men who receive androgen-deprivation therapy (ADT) for prostate cancer experience several side effects from this treatment. A few recent studies have examined the cognitive implications of ADT and how they impact a patient’s treatment decision-making, occupational pursuits, and quality of life. For this report, the authors explored possible mechanisms for this association, reviewed research in animal studies and aging men, and examined the growing literature focused on the relation between ADT and cognitive functioning in patients with prostate cancer.
A systematic literature search was conducted using the PubMed and Information Sciences Institute Web of Knowledge-Web of Science databases to identify relevant studies that investigated the relation between ADT in men with prostate cancer and its cognitive effects.
Testosterone and its derivatives may have an impact on cognition through several mechanisms in the brain, as supported by studies of animals and in aging men. Studies that researched the impact of ADT on cognition in patients with prostate cancer patients were designed relatively well but suffered from small sample sizes. Between 47% and 69% of men on ADT declined in at least 1 cognitive area, most commonly in visuospatial abilities and executive functioning. Some studies reported contradictory results with increased functioning in verbal memory.
There is a strong argument that androgen-ablation therapy is linked to subtle but significant cognitive declines in men with prostate cancer. The authors believe that clinicians should become aware of this correlation as the use of ADT increases and should inform and monitor patients for this possible side effect of treatment.
PMCID: PMC4333639  PMID: 18666210
altered cognitive function; androgen ablation; dihydrotestosterone; estradiol; prostate cancer; quality of life; testosterone
2.  Communication and Intimacy-Enhancing Interventions for Men Diagnosed with Prostate Cancer and Their Partners 
The journal of sexual medicine  2013;10(0 1):127-132.
The sexual dysfunction following prostate cancer treatments often leads to a reduction in intimate contact for couples. A number of psychosocial interventions have been developed to enhance intimacy in these couples. This paper reviews three of these interventions and is a summary of a presentation given as part of a symposium at the 2011 Cancer Survivorship and Sexual Health Meeting.
The goal of this presentation was to: (i) review three types of psychosocial interventions; and (ii) describe the methodological issues highlighted by these interventions.
Main Outcome Measures
Validated measures of relationship intimacy and communication.
To be selected, the interventions had to be: a randomized control trial, focus on a couples approach to therapy, and report at least one relationship outcome.
The results were not consistent within or across studies, and suggest that some specific aspects of the interventions may be helpful for the patient, while other aspects of the studies may be helpful for the partner. The Northouse et al. study suggests that partners may benefit from a focus on couple work, as compared to the patient. The Canada et al. study indicates that when focusing on sexual functioning, working with a couple did not show significant benefit compared to working with a man alone. The study did show, however, that a sexual-based intervention can improve the use of erectile dysfunction treatments and suggests patients may benefit from specific focus on side effects of treatment. The Manne et al. study highlights the importance of targeting these interventions to couples who report distress, and for distressed couples, an intervention can show positive results.
Intimacy enhancing interventions can be effective for couples, while the partners may benefit more from couples work; the patients may benefit more from focus on specific side effects.
PMCID: PMC4324570  PMID: 23387918
Prostate; Cancer; Treatment; Psychosocial Interventions for Men with Prostate Cancer
3.  Psychological Correlates of Sexual Dysfunction in Female Rectal and Anal Cancer Survivors: Analysis of Baseline Intervention Data 
The journal of sexual medicine  2013;10(10):2539-2548.
Sexual dysfunction represents a complex and multifactorial construct that can affect both men and women and has been noted to often deteriorate significantly after treatment for rectal and anal cancer. Despite this, it remains an understudied, underreported and undertreated issue in the field of cancer survivorship.
This study examined the characteristics of women enrolled in an intervention trial to treat sexual dysfunction, and explored the relationship between sexual functioning and psychological well-being.
Main Outcomes Measures
Quality of life (EORTC-QLQ-C30 & QLQ-CR38), sexual functioning (FSFI) and psychological well-being (BSI Depression/Anxiety, IES-R, CR-38 Body Image).
There were 70 female post-treatment anal or rectal cancer survivors assessed as part of the current study. Participants were enrolled in a randomized intervention trial to treat sexual dysfunction and completed outcome measures prior to randomization.
Women enrolled in the study intervention were on average 55 years old, predominantly Caucasian (79%), married (57%) and a median of 4 years post-primary treatment. For those reporting sexual activity at baseline (N=41), sexual dysfunction was associated with a range of specific measures of psychological well-being, all in the hypothesized direction. The Sexual/Relationship Satisfaction subscale was associated with all measures of psychological well-being (r=−.45 to −.70, all p<.01). Body image, anxiety and cancer-specific post-traumatic distress were notable in their association with subscales of sexual functioning, while a global quality of life measure was largely unrelated.
For sexually-active female rectal and anal cancer survivors enrolled in a sexual health intervention, sexual dysfunction was significantly and consistently associated with specific measures of psychological well-being, most notably Sexual/Relationship Satisfaction. These results suggest that sexual functioning may require focused assessment by providers, beyond broad quality of life assessments, and that attention to Sexual/Relationship Satisfaction may be critical in the development and implementation of interventions for this cohort of patients.
PMCID: PMC3706574  PMID: 23551928
Sexual Dysfunction; Sexual Health; Rectal Cancer; Psychological Distress
5.  Erectile Function Recovery Rate after Radical Prostatectomy: A Meta-Analysis 
The journal of sexual medicine  2009;6(9):2538-2546.
Erectile function recovery (EFR) rates after radical prostatectomy (RP) vary greatly based on a number of factors, such as erectile dysfunction (ED) definition, data acquisition means, time-point postsurgery, and population studied.
To conduct a meta-analysis of carefully selected reports from the available literature to define the EFR rate post-RP.
Main Outcome Measures
EFR rate after RP.
An EMBASE and MEDLINE search was conducted for the time range 1985–2007. Articles were assessed blindly by strict inclusion criteria: report of EFR data post-RP, study population ≥50 patients, ≥1 year follow-up, nerve-sparing status declared, no presurgery ED, and no other prostate cancer therapy. Meta-analysis was conducted to determine the EFR rate and relative risks (RR) for dichotomous subgroups.
A total of 212 relevant studies were identified; only 22 (10%) met the inclusion criteria and were analyzed (9,965 RPs, EFR data: 4,983 subjects). Mean study population size: 226.5, standard deviation = 384.1 (range: 17–1,834). Overall EFR rate was 58%. Single center series publications (k = 19) reported a higher EFR rate compared with multicenter series publications (k = 3): 60% vs. 33%, RR = 1.82, P = 0.001. Studies reporting ≥18-month follow-up (k = 10) reported higher EFR rate vs. studies with <18-month follow-up (k = 12), 60% vs. 56%, RR = 1.07, P = 0.02. Open RP (k = 16) and laparoscopic RP (k = 4) had similar EFR (57% vs. 58%), while robot-assisted RP resulted in a higher EFR rate (k = 2), 73% compared with these other approaches, P = 0.001. Patients <60 years old had a higher EFR rate vs. patients ≥60 years, 77% vs. 61%, RR = 1.26, P = 0.001.
These data indicate that most of the published literature does not meet strict criteria for reporting post-RP EFR. Single and multiple surgeon series have comparable EFR rates, but single center studies have a higher EFR. Younger men have higher EFR and no significant difference in EFR between ORP and LRP is evident.
PMCID: PMC4097184  PMID: 19515209
Erectile Function; Radical Prostatectomy; Meta-Analysis; Factors Affecting Erection Recovery Rate
6.  The Human Alpha Defensin HD5 Neutralizes JC Polyomavirus Infection by Reducing Endoplasmic Reticulum Traffic and Stabilizing the Viral Capsid 
Journal of Virology  2014;88(2):948-960.
Progressive multifocal leukoencephalopathy (PML) is a fatal disease with limited treatment options, both clinically and in the research pipeline. Potential therapies would target and neutralize its etiologic agent, JC polyomavirus (JCPyV). The innate immune response to JCPyV infection has not been studied, and little is known about the initial host response to polyomavirus infection. This study examined the ability of a human alpha defensin, HD5, to neutralize JCPyV infection in human fetal glial cells. We show that HD5, by binding to the virion, blocks infection. The JCPyV-HD5 complexes bind to and enter host cells but are reduced in their ability to reach the endoplasmic reticulum (ER), where virions are normally uncoated. Furthermore, HD5 binding to the virion stabilizes the capsid and prevents genome release. Our results show that HD5 neutralizes JCPyV infection at an early postentry step in the viral life cycle by stabilizing the viral capsid and disrupting JCPyV trafficking. This study provides a naturally occurring platform for developing antivirals to treat PML and also expands on the known capabilities of human defensins.
PMCID: PMC3911681  PMID: 24198413
7.  5-HT2 Receptors Facilitate JC Polyomavirus Entry 
Journal of Virology  2013;87(24):13490-13498.
The human JC polyomavirus (JCPyV) causes the rapidly progressing demyelinating disease progressive multifocal leukoencephalopathy (PML). The disease occurs most often in individuals with AIDS but also occurs in individuals receiving immunomodulatory therapies for immune-related diseases such as multiple sclerosis. JCPyV infection of host cells requires the pentasaccharide lactoseries tetrasaccharide c (LSTc) and the serotonin receptor 5-hydroxytryptamine (5-HT) receptor 5-HT2AR. While LSTc is involved in the initial attachment of virus to cells via interactions with VP1, the mechanism by which 5-HT2AR contributes to infection is not clear. To further define the roles of serotonin receptors in infection, HEK293A cells, which are poorly permissive to JCPyV, were transfected with 14 different isoforms of serotonin receptor. Only 5-HT2 receptors were found to support infection by JCPyV. None of the other 11 isoforms of serotonin receptor supported JCPyV infection. Expression of 5-HT2 receptors did not increase binding of JCPyV to cells, but this was not unexpected, given that the cells uniformly expressed the major attachment receptor, LSTc. Infection of these cells remained sensitive to inhibition with soluble LSTc, confirming that LSTc recognition is required for JCPyV infection. Virus internalization into HEK293A cells was significantly and specifically enhanced when 5HT2 receptors were expressed. Taken together, these data confirm that the carbohydrate LSTc is the attachment receptor for JCPyV and that the type 2 serotonin receptors contribute to JCPyV infection by facilitating entry.
PMCID: PMC3838264  PMID: 24089568
8.  Capsid Antibodies to Different Adeno-Associated Virus Serotypes Bind Common Regions 
Journal of Virology  2013;87(16):9111-9124.
Interactions between viruses and the host antibody immune response are critical in the development and control of disease, and antibodies are also known to interfere with the efficacy of viral vector-based gene delivery. The adeno-associated viruses (AAVs) being developed as vectors for corrective human gene delivery have shown promise in clinical trials, but preexisting antibodies are detrimental to successful outcomes. However, the antigenic epitopes on AAV capsids remain poorly characterized. Cryo-electron microscopy and three-dimensional image reconstruction were used to define the locations of epitopes to which monoclonal fragment antibodies (Fabs) against AAV1, AAV2, AAV5, and AAV6 bind. Pseudoatomic modeling showed that, in each serotype, Fabs bound to a limited number of sites near the protrusions surrounding the 3-fold axes of the T=1 icosahedral capsids. For the closely related AAV1 and AAV6, a common Fab exhibited substoichiometric binding, with one Fab bound, on average, between two of the three protrusions as a consequence of steric crowding. The other AAV Fabs saturated the capsid and bound to the walls of all 60 protrusions, with the footprint for the AAV5 antibody extending toward the 5-fold axis. The angle of incidence for each bound Fab on the AAVs varied and resulted in significant differences in how much of each viral capsid surface was occluded beyond the Fab footprints. The AAV-antibody interactions showed a common set of footprints that overlapped some known receptor-binding sites and transduction determinants, thus suggesting potential mechanisms for virus neutralization by the antibodies.
PMCID: PMC3754064  PMID: 23760240
9.  A Retrograde Trafficking Inhibitor of Ricin and Shiga-Like Toxins Inhibits Infection of Cells by Human and Monkey Polyomaviruses 
mBio  2013;4(6):e00729-13.
Polyomaviruses are ubiquitous pathogens that cause severe disease in immunocompromised individuals. JC polyomavirus (JCPyV) is the causative agent of the fatal demyelinating disease progressive multifocal leukoencephalopathy (PML), whereas BK polyomavirus (BKPyV) causes polyomavirus-induced nephropathy and hemorrhagic cystitis. Vaccines or antiviral therapies targeting these viruses do not exist, and treatments focus on reducing the underlying causes of immunosuppression. We demonstrate that retro-2cycl, an inhibitor of ricin and Shiga-like toxins (SLTs), inhibits infection by JCPyV, BKPyV, and simian virus 40. Retro-2cycl inhibits retrograde transport of polyomaviruses to the endoplasmic reticulum, a step necessary for productive infection. Retro-2cycl likely inhibits polyomaviruses in a way similar to its ricin and SLT inhibition, suggesting an overlap in the cellular host factors used by bacterial toxins and polyomaviruses. This work establishes retro-2cycl as a potential antiviral therapy that broadly inhibits polyomaviruses and possibly other pathogens that use retrograde trafficking.
The human polyomaviruses JC polyomavirus (JCPyV) and BK polyomavirus (BKPyV) cause rare but severe diseases in individuals with reduced immune function. During immunosuppression, JCPyV disseminates from the kidney to the central nervous system and destroys oligodendrocytes, resulting in the fatal disease progressive multifocal leukoencephalopathy. Kidney transplant recipients are at increased risk of BKPyV-induced nephropathy, which results in kidney necrosis and loss of the transplanted organ. There are currently no effective therapies for JCPyV and BKPyV. We show that a small molecule named retro-2cycl protects cells from infection with JCPyV and BKPyV by inhibiting intracellular viral transport. Retro-2cycl treatment reduces viral spreading in already established infections and may therefore be able to control infection in affected patients. Further optimization of retro-2cycl may result in the development of an effective antiviral therapy directed toward pathogens that use retrograde trafficking to infect their hosts.
PMCID: PMC3892778  PMID: 24222489
10.  Burden and Benefit of Psychosocial Research at the End of Life 
Journal of palliative medicine  2008;11(4):627-632.
The impact of psychosocial research participation has not been examined systematically in palliative care settings. Concerns are often raised regarding the potential for distress among terminally ill patients. This is particularly true when death and dying are the focus of research. Therefore, it is important to understand the specific ways psychosocial research could potentially harm or be helpful to participants.
To assess the burden and benefits of participation in psychosocial research addressing end-of-life issues among patients receiving inpatient palliative care.
Sixty-eight terminally ill patients with cancer who had an average life expectancy of less than 2 months, were administered a brief self-report questionnaire to assess whether participation in psychosocial research was burdensome and/or beneficial. The specific factors that contributed to their perceptions were also identified.
The majority of patients reported no burden associated with participation (75%) and found the experience as moderately to highly beneficial (68%). Factors most frequently identified as burdensome included the length of the interview (21%), structure of the questionnaires (18%), and difficulty discussing end-of life issues (12%). Although some patients reported some distress while discussing end-of-life issues (19%), few endorsed a high level of distress (6%). Factors most frequently identified as beneficial were the social interaction (75%), sense of contributing to society (57%), and the opportunity to discuss their illness (47%).
Participants in psychosocial end-of-life research are unlikely to experience significant burden from participation and, in fact, may benefit.
PMCID: PMC3717570  PMID: 18454616
11.  Molecular Biology, Epidemiology, and Pathogenesis of Progressive Multifocal Leukoencephalopathy, the JC Virus-Induced Demyelinating Disease of the Human Brain 
Clinical Microbiology Reviews  2012;25(3):471-506.
Summary: Progressive multifocal leukoencephalopathy (PML) is a debilitating and frequently fatal central nervous system (CNS) demyelinating disease caused by JC virus (JCV), for which there is currently no effective treatment. Lytic infection of oligodendrocytes in the brain leads to their eventual destruction and progressive demyelination, resulting in multiple foci of lesions in the white matter of the brain. Before the mid-1980s, PML was a relatively rare disease, reported to occur primarily in those with underlying neoplastic conditions affecting immune function and, more rarely, in allograft recipients receiving immunosuppressive drugs. However, with the onset of the AIDS pandemic, the incidence of PML has increased dramatically. Approximately 3 to 5% of HIV-infected individuals will develop PML, which is classified as an AIDS-defining illness. In addition, the recent advent of humanized monoclonal antibody therapy for the treatment of autoimmune inflammatory diseases such as multiple sclerosis (MS) and Crohn's disease has also led to an increased risk of PML as a side effect of immunotherapy. Thus, the study of JCV and the elucidation of the underlying causes of PML are important and active areas of research that may lead to new insights into immune function and host antiviral defense, as well as to potential new therapies.
PMCID: PMC3416490  PMID: 22763635
12.  The VP1 subunit of JC polyomavirus recapitulates early events in viral trafficking and is a novel tool to study polyomavirus entry 
Virology  2012;428(1):30-40.
JC polyomavirus (JCV) is an important human pathogen that causes the fatal demyelinating disease progressive multifocal leukoencephalopathy (PML). In this study we further delineate the early events of JCV entry in human glial cells and demonstrate that a pentameric subunit of the viral capsid is able to recapitulate early events in viral trafficking. We show that JCV traffics to the endoplasmic reticulum (ER) by 6 h post infection, and that VP1 pentamers arrive at the ER with similar kinetics. Further, this JCV localization to the ER is critical for infection, as treatment of cells with agents that prevent ER trafficking, ER function, or ER quality control reduce JCV infectivity. These pentamers represent a new tool to study polyomavirus entry, and will be particularly useful in studying recently identified polyomaviruses that are difficult to propagate.
PMCID: PMC3569719  PMID: 22516137
JC polyomavirus; Endoplasmic reticulum; Trafficking; Endocytosis
13.  Meaning-centered group psychotherapy for patients with advanced cancer: a pilot randomized controlled trial 
Psycho-oncology  2010;19(1):21-28.
An increasingly important concern for clinicians who care for patients at the end of life is their spiritual well-being and sense of meaning and purpose in life. In response to the need for short-term interventions to address spiritual well-being, we developed Meaning Centered Group Psychotherapy (MCGP) to help patients with advanced cancer sustain or enhance a sense of meaning, peace and purpose in their lives, even as they approach the end of life.
Patients with advanced (stage III or IV) solid tumor cancers (N = 90) were randomly assigned to either MCGP or a supportive group psychotherapy (SGP). Patients were assessed before and after completing the 8-week intervention, and again 2 months after completion. Outcome assessment included measures of spiritual well-being, meaning, hopelessness, desire for death, optimism/pessimism, anxiety, depression and overall quality of life.
MCGP resulted in significantly greater improvements in spiritual well-being and a sense of meaning. Treatment gains were even more substantial (based on effect size estimates) at the second follow-up assessment. Improvements in anxiety and desire for death were also significant (and increased over time). There was no significant improvement on any of these variables for patients participating in SGP.
MCGP appears to be a potentially beneficial intervention for patients’ emotional and spiritual suffering at the end of life. Further research, with larger samples, is clearly needed to better understand the potential benefits of this novel intervention.
PMCID: PMC3648880  PMID: 19274623
psychotherapy; meaning; spiritual well-being; palliative care; existential
14.  Methylphenidate for Fatigue in Ambulatory Men with Prostate Cancer 
Cancer  2010;116(21):5102-5110.
Fatigue is a highly prevalent and clinically significant symptom of advanced prostate cancer. To date, however, there are no published controlled trials of interventions for fatigue in men with prostate cancer.
This six-week, randomized, double-blind, placebo-controlled design, evaluated the efficacy of methylphenidate to treat fatigue in prostate cancer patients. Inclusion criteria included men with advanced prostate cancer and the presence of moderate to severe fatigue. Patients with major depression, hypothyroidism, uncontrolled hypertension, arrhythmia or anemia were excluded. Fatigue levels, blood pressure, pulse and other safety concerns were monitored regularly.
Thirty-two subjects were randomized to methylphenidate (N=16) or placebo (N=16). Brief Fatigue Inventory (BFI) total scores significantly decreased for both groups, however the methylphenidate group, as compared to placebo, reported greater decrease on BFI severity scores (p=.03) and a trend toward greater decrease on BFI total scores (p=.07). A significantly greater number of subjects in the methylphenidate group vs. the placebo group demonstrated clinically significant improvement in fatigue on total BFI scores (7/10 vs. 3/13) and BFI severity scores (8/10 vs. 3/13). Importantly, six subjects in the methylphenidate group discontinued due to increased blood pressure or tachycardia. There were no serious adverse events.
Methylphenidate is effective in treating fatigue in men with prostate cancer; however, oncologists need to monitor for possible pulse and blood pressure elevations.
PMCID: PMC3632439  PMID: 20665492
15.  The Mub1/Ubr2 Ubiquitin Ligase Complex Regulates the Conserved Dsn1 Kinetochore Protein 
PLoS Genetics  2013;9(2):e1003216.
The kinetochore is the macromolecular complex that assembles onto centromeric DNA and orchestrates the segregation of duplicated chromosomes. More than 60 components make up the budding yeast kinetochore, including inner kinetochore proteins that bind to centromeric chromatin and outer proteins that directly interact with microtubules. However, little is known about how these components assemble into a functional kinetochore and whether there are quality control mechanisms that monitor kinetochore integrity. We previously developed a method to isolate kinetochore particles via purification of the conserved Dsn1 kinetochore protein. We find that the Mub1/Ubr2 ubiquitin ligase complex associates with kinetochore particles through the CENP-CMif2 protein. Although Mub1/Ubr2 are not stable kinetochore components in vivo, they regulate the levels of the conserved outer kinetochore protein Dsn1 via ubiquitylation. Strikingly, a deletion of Mub1/Ubr2 restores the levels and viability of a mutant Dsn1 protein, reminiscent of quality control systems that target aberrant proteins for degradation. Consistent with this, Mub1/Ubr2 help to maintain viability when kinetochores are defective. Together, our data identify a previously unknown regulatory mechanism for the conserved Dsn1 kinetochore protein. We propose that Mub1/Ubr2 are part of a quality control system that monitors kinetochore integrity, thus ensuring genomic stability.
Author Summary
The flawless execution of cell division is essential to the survival of all organisms. The loss or gain of a single chromosome, the state called aneuploidy, is a hallmark of cancer cells and is the leading cause of spontaneous miscarriages and hereditary birth defects. Segregation is mediated by the kinetochore, the macromolecular complex that assembles on each chromosome and attaches to spindle microtubules to pull chromosomes to opposite poles when cells divide. It is therefore critical to understand how kinetochores are assembled and maintained. Here, we find that the levels of a conserved kinetochore protein are regulated by proteolysis. We propose that cells have quality control systems that ensure kinetochore integrity and thus genome stability.
PMCID: PMC3567142  PMID: 23408894
16.  Medical Student Sexuality: How Sexual Experience and Sexuality Training Impact U.S. and Canadian Medical Students’ Comfort in Dealing with Patients’ Sexuality in Clinical Practice 
To determine factors associated with students’ comfort in addressing patients’ sexuality in the clinical context.
The authors invited students enrolled in MD-degree-granting and osteopathic medical schools in the United States and Canada to participate in an anonymous Internet survey between February and July 2008. The survey assessed ethnodemographic factors and sexual history. Respondents also completed the Center for Epidemiologic Studies Depression Scale. Male respondents completed the International Index of Erectile Function and the Premature Ejaculation Diagnostic Tool. Female respondents completed the Female Sexual Function Index and the Index of Sex Life. The authors used descriptive statistics, ANOVA, and multivariable logistic regression to analyze responses.
The authors’ analyses included 2,261 completed survey responses: 910 from men, 1,343 from women, and 8 from individuals who self-identified as “other” gendered. Over 53% of respondents (n = 1,206) stated that they felt they had not received sufficient training in medical school to address sexual concerns clinically. Despite this, 81% of students (n = 1,827) reported feeling comfortable dealing with their patients’ sexuality issues. Students with limited sexual experience, students at risk for sexual problems, and students who felt that they had not been trained adequately were less likely to report being comfortable talking to patients about sexual health issues.
Perception of inadequate sexuality training in medical school and personal issues pertaining to sex may be associated with students’ difficulty in addressing patients’ sexuality. Adequate training is preeminently associated with feeling comfortable addressing patients’ sexuality and should be a priority for medical education.
PMCID: PMC3565617  PMID: 20671459
17.  The structure of avian polyomavirus reveals variably sized capsids, nonconserved inter-capsomere interactions, and a possible location of the minor capsid protein VP4 
Virology  2011;411(1):142-152.
Avian polyomavirus (APV) causes a fatal, multi-organ disease among several bird species. Using cryogenic electron microscopy and other biochemical techniques, we investigated the structure of APV and compared it to that of mammalian polyomaviruses, particularly JC polyomavirus and simian virus 40. The structure of the pentameric major capsid protein (VP1) is mostly conserved; however, APV VP1 has a unique, truncated C-terminus that eliminates an intercapsomere-connecting β-hairpin observed in other polyomaviruses. We postulate that the terminal β-hairpin locks other polyomavirus capsids in a stable conformation and that absence of the hairpin leads to the observed capsid size variation in APV. Plug-like density features were observed at the base of the VP1 pentamers, consistent with the known location of minor capsid proteins VP2 and VP3. However, the plug density is more prominent in APV and may include VP4, a minor capsid protein unique to bird polyomaviruses.
PMCID: PMC3057058  PMID: 21239031
arginine; capsomere connections; cryo-electron microscopy; homology model; human JC polyomavirus; simian virus 40; size-exclusion chromatography; three-dimensional reconstruction; virus assembly; virus structure
18.  Depression and Barriers to Mental Health Care in Older Cancer Patients 
To review the literature on depression in cancer patients with a particular focus on depression assessment and barriers to mental health treatment in older cancer patients.
We conducted a review of the literature on depression and barriers to mental health treatment in older cancer patients.
Depression is prevalent in cancer patients. However, little is known about prevalence rates of depression in older adults with cancer, assessing depression in older cancer patients and barriers that impede proper mental health treatment in this sample.
Improved diagnostic clarity and a better understanding of barriers to mental health treatment can help clarify and facilitate mental health referrals and ultimately improve access to care among older cancer patients in need. Continuing to consider the complexities associated with diagnosing depression in older cancer patients is necessary. Further work may be needed to develop new diagnostic measures for such detection, determine the prevalence of depression among older cancer and ways in which to overcome barriers to mental health care.
PMCID: PMC3052769  PMID: 21157847
depression; cancer; older; barriers to mental health treatment; assessment
19.  Structure-function analysis of the human JC polyomavirus establishes the LSTc pentasaccharide as a functional receptor motif 
Cell host & microbe  2010;8(4):309-319.
The human JC polyomavirus (JCV) causes a fatal demyelinating disease, Progressive Multifocal Leukoencephalopathy (PML), in immunocompromised individuals. Current treatment options for PML are inadequate. Sialylated oligosaccharides and the serotonin receptor are known to be necessary for JCV entry, but the molecular interactions underlying JCV attachment remain unknown. Using glycan array screening and viral infectivity assays, we identify a linear sialylated pentasaccharide with the sequence NeuNAc-α2,6-Gal-β1,4-GlcNAc-β1,3-Gal-β1,4-Glc (LSTc) present on host glycoproteins and glycolipids as a specific JCV recognition motif. The crystal structure of the JCV capsid protein VP1 was solved alone and in complex with LSTc. It reveals extensive interactions with the terminal sialic acid of the LSTc motif and specific recognition of an extended conformation of LSTc. Mutations in the JCV oligosaccharide binding sites abolish cell attachment, viral spread and infectivity, further validating the importance of this interaction. Our findings provide a powerful platform for the development of antiviral compounds.
PMCID: PMC2957469  PMID: 20951965
20.  Tension directly stabilizes reconstituted kinetochore-microtubule attachments 
Nature  2010;468(7323):576-579.
Kinetochores are macromolecular machines that couple chromosomes to dynamic microtubule tips during cell division, thereby generating force to segregate the chromosomes1,2. Accurate segregation depends on selective stabilization of correct ‘bi-oriented’ kinetochore-microtubule attachments, which come under tension due to opposing forces exerted by microtubules3. Tension is thought to stabilize these bi-oriented attachments indirectly, by suppressing the destabilizing activity of a kinase, Aurora B4,5. However, a complete mechanistic understanding of the role of tension requires reconstitution of kinetochore-microtubule attachments for biochemical and biophysical analyses in vitro. Here we show that native kinetochore particles retaining the majority of kinetochore proteins can be purified from budding yeast and used to reconstitute dynamic microtubule attachments. Individual kinetochore particles maintain load-bearing associations with assembling and disassembling ends of single microtubules for >30 min, providing a close match to the persistent coupling seen in vivo between budding yeast kinetochores and single microtubules6. Moreover, tension increases the lifetimes of the reconstituted attachments directly, via a catch bond-like mechanism that does not require Aurora B7-10. Based on these findings, we propose that tension selectively stabilizes proper kinetochore-microtubule attachments in vivo through a combination of direct mechanical stabilization and tension-dependent phosphoregulation.
PMCID: PMC3108429  PMID: 21107429
21.  Untangling the Complexities of Depression Diagnosis in Older Cancer Patients 
The oncologist  2009;14(1):60-66.
This review article discusses the complexities of diagnosing depression in older, geriatric cancer patients. There has been little research conducted with this population on the assessment, recognition and treatment of depression, and thus increased attention is required to improve care for these individuals. Depressive symptoms often manifest themselves differently in both cancer patients and in older patients, and therefore a modified and adapted way of assessment must be employed when thinking about diagnosing and treating these patients.
PMCID: PMC3051280  PMID: 19144682
Depression Diagnosis; Cancer; Geriatrics
22.  Cancer-Related Communication, Relationship Intimacy, and Psychological Distress Among Couples Coping with Localized Prostate Cancer 
The present study evaluated intimacy as a mechanism for the effects of relationship-enhancing (self-disclosure, mutual constructive communication) and relationship-compromising communication (holding back, mutual avoidance, and demand-withdraw communication) on couples' psychological distress.
Seventy-five men diagnosed with localized prostate cancer in the past year and their partners completed surveys about communication, intimacy, and distress.
Multi-level models with the couple as unit of analyses indicated that the association between mutual constructive communication, mutual avoidance, and patient demand-partner withdraw and distress could be accounted for by their influence on relationship intimacy. Self-disclosure, holding back, and partner demand-patient withdraw did not mediate the associations between communication and distress.
These findings indicate that the way in which couples talk about as well as the degree to which one or both partners avoid talking about cancer-related concerns can either facilitate or reduce relationship closeness, and that it is largely by this mechanism that these three communication strategies impact psychological distress.
Implications for Cancer Survivors
Relationship intimacy and how patients and partners communicate to achieve this intimacy is important for the psychological adjustment of early stage prostate cancer survivors and their partners.
PMCID: PMC2828868  PMID: 19967408
Couple communication; relationship intimacy; prostate cancer
23.  Are Gold Standard Depression Measures Appropriate for Use in Geriatric Cancer Patients? A Systematic Evaluation of Self-Report Depression Instruments Used With Geriatric, Cancer, and Geriatric Cancer Samples 
Journal of Clinical Oncology  2009;28(2):348-356.
Geriatric issues in cancer are becoming prominent. Depression is a significant concern for both the elderly and patients with cancer, yet identifying depression in these patients is difficult and often leads to under-recognition. We conducted a systematic review to determine which depression instruments are appropriate for use in geriatric patients with cancer.
We identified the most commonly used self-report depression instruments. We then used the criteria established in the US Food and Drug Administration Draft Guidance on Patient-Reported Outcome Measures to determine the extent of validation evidence of these measures in geriatric cancer populations. Finally, we determined which instruments captured depressive symptoms that are common among elderly patients with cancer.
Eight measures were selected as the most commonly used instruments. These were the Beck Depression Inventory-II, Brief Symptom Inventory-18, Center for Epidemiologic Studies–Depression Scale, Geriatric Depression Scale-15, Hospital Anxiety and Depression Scale, Patient Health Questionnaire-9, Profile of Mood States–Short Form, and Zung Self-Rating Depression Scale. Many have been validated for use with geriatric adults and patients with cancer; however, data addressing content validity and responder definition were lacking. To date, there is no validation information for geriatric patients with cancer. Furthermore, symptom profile analysis revealed that these measures do not identify many symptoms signaling depression in geriatric patients with cancer.
The validation evidence for use of common depression instruments in geriatric patients with cancer is lacking. This, and the possibility that these measures may not assess common depressive symptoms in geriatric patients with cancer, questions the adequacy of these scales in this population.
PMCID: PMC2815722  PMID: 19996030
24.  The role of spirituality in the relationship between religiosity and depression in prostate cancer patients 
This study aims to develop a theoretical framework of the relationship among religiosity, spirituality, and depression, potentially explaining the often mixed and inconsistent associations between religiosity and depression.
In this cross-sectional study, 367 men (average age of 66 ± 9 years) with prostate cancer completed measures of religiosity (extrinsic/intrinsic), spirituality (FACIT Spiritual Well-Being Scale), quality of life (FACT-G) and depression (Hospital Anxiety and Depression Scale).
There was a small relationship between intrinsic religiosity and depression (r = −0.23, p<0.05) but a strong association between spirituality and depression (r = −0.58, p<0.01). Using a mediation model, the meaning/peace subscale of the spirituality measure mediated the relationship between intrinsic religiosity and depression. This model controlled for age, marital status, stage of disease, time since diagnosis, hormone therapy, quality of life, and anxiety.
When examining religiosity and spirituality, the main component that may help reduce depression is a sense of meaning and peace. These results highlight the potential importance of developing a patient’s sense of meaning through activities/interventions (not exclusive to religious involvement) to achieve this goal.
PMCID: PMC2877207  PMID: 19806413
25.  Distress in Older Patients With Cancer 
Journal of Clinical Oncology  2009;27(26):4346-4351.
To determine the predictors of distress in older patients with cancer.
Patients and Methods
Patients age ≥ 65 years with a solid tumor or lymphoma completed a questionnaire that addressed these geriatric assessment domains: functional status, comorbidity, psychological state, nutritional status, and social support. Patients self-rated their level of distress on a scale of zero to 10 using a validated screening tool called the Distress Thermometer. The relationship between distress and geriatric assessment scores was examined.
The geriatric assessment questionnaire was completed by 245 patients (mean age, 76 years; standard deviation [SD], 7 years; range, 65 to 95 years) with cancer (36% stage IV; 71% female). Of these, 87% also completed the Distress Thermometer, with 41% (n = 87) reporting a distress score of ≥ 4 on a scale of zero to 10 (mean score, 3; SD, 3; range, zero to 10). Bivariate analyses demonstrated an association between higher distress (≥ 4) and poorer physical function, increased comorbid medical conditions, poor eyesight, inability to complete the questionnaire alone, and requiring more time to complete the questionnaire. In a multivariate regression model based on the significant bivariate findings, poorer physical function (increased need for assistance with instrumental activities of daily living [P = .015] and lower physical function score on the Medical Outcomes Survey [P = .018]) correlated significantly with a higher distress score.
Significant distress was identified in 41% of older patients with cancer. Poorer physical function was the best predictor of distress. Further studies are needed to determine whether interventions that improve or assist with physical functioning can help to decrease distress in older adults with cancer.
PMCID: PMC2799049  PMID: 19652074

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