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1.  Men's Experience with Penile Rehabilitation Following Radical Prostatectomy: A Qualitative Study with the Goal of Informing a Therapeutic Intervention 
Psycho-oncology  2015;24(12):1646-1654.
Erectile rehabilitation (ER) following radical prostatectomy (RP) is considered an essential component to help men regain erectile functioning; however many men have difficulty adhering to this type of a program. This qualitative study explored men's experience with ER, erectile dysfunction (ED), and ED treatments to inform a psychological intervention designed to help men adhere to ER post-RP.
Thirty men, one to three years post-RP, who took part in an ER program, participated in one of four focus groups. Thematic analysis was used to identify the primary themes.
Average age was 59 (SD=7); mean time since surgery was 26 months (SD=6). Six primary themes emerged: 1) frustration with the lack of information about post-surgery ED; 2) negative emotional impact of ED and avoidance of sexual situations; 3) negative emotional experience with penile injections and barriers leading to avoidance; 4) the benefit of focusing on the long-term advantage of ER versus short-term anxiety; 5) using humor to help cope; and 6) the benefit of support from partners and peers.
Men's frustration surrounding ED can lead to avoidance of sexual situations and ED treatments, which negatively impact men's adherence to an ER program. The theoretical construct of Acceptance and Commitment Therapy (ACT) was used to place the themes into a framework to conceptualize the mechanisms underlying both avoidance and adherence in this population. As such, ACT has the potential to serve as a conceptual underpinning of a psychological intervention to help men reduce avoidance to penile injections and adhere to an ER program.
PMCID: PMC4765804  PMID: 25707812
prostate cancer; erectile dysfunction; sexual function; erectile rehabilitation
2.  JC Polyomavirus Attachment, Entry, and Trafficking: Unlocking the Keys to a Fatal Infection 
Journal of neurovirology  2014;21(6):601-613.
The human JC polyomavirus (JCPyV) causes a lifelong persistent infection in the reno-urinary tract in the majority of the adult population worldwide. In healthy individuals infection is asymptomatic, while in immunocompromised individuals the virus can spread to the central nervous system and cause a fatal demyelinating disease known as progressive multifocal leukoencephalopathy (PML). There are currently very few treatment options for this rapidly progressing and devastating disease. Understanding the basic biology of JCPyV-host cell interactions is critical for the development of therapeutic strategies to prevent or treat PML. Research in our laboratory has focused on gaining a detailed mechanistic understanding of the initial steps in the JCPyV life cycle in order to define how JCPyV selectively targets cells in the kidney and brain. JCPyV requires sialic acids to attach to host cells and initiate infection, and JCPyV demonstrates specificity for the oligosaccharide lactoseries tetrasaccharide c (LSTc) with an α2,6-linked sialic acid. Following viral attachment, JCPyV entry is facilitated by the 5-hydroxytryptamine (5-HT)2 family of serotonin receptors via clathrin-dependent endocytosis. JCPyV then undergoes retrograde transport to the endoplasmic reticulum (ER) where viral disassembly begins. A novel retrograde transport inhibitor termed Retro-2cycl prevents trafficking of JCPyV to the ER and inhibits both initial virus infection and infectious spread in cell culture. Understanding the molecular mechanisms by which JCPyV establishes infection will open up new avenues for the prevention or treatment of virus-induced disease.
PMCID: PMC4312552  PMID: 25078361
JC polyomavirus; PML; sialic acid; LSTc; serotonin receptor; Retro-2cycl
3.  Towards a new conceptualization of depression in older adult cancer patients: a review of the literature 
Aging & mental health  2015;20(12):1230-1242.
Identifying depression in older adults with cancer presents a set of unique challenges, as it combines the confounding influences of cancer and its treatment with the developmental changes associated with aging. This paper reviews the phenomenology of depression in older adults, and individuals diagnosed with cancer.
PsychInfo, PubMed, Web of Science, and Google Scholar databases were searched for English-language studies addressing the phenomenology, symptoms, or assessment of depression in older adults and those with cancer.
The Diagnostic and Statistical Manual for Mental Disorders (DSM) criteria that appear to be relevant to both older adults and cancer patients are anhedonia, concentration difficulties, sleep disturbances, psychomotor retardation/agitation, and loss of energy. Possible alternative criteria that may be important considerations included constructs such as loss of purpose, loneliness, and irritability in older adults. Among cancer patients, tearfulness, social withdrawal, and not participating in treatment despite ability to do so were identified as potentially important symptoms.
Current DSM criteria may not adequately assess depression in older cancer patients and alternative criteria may be important to inform the understanding and identification of depression in this population. Enhancing diagnostic accuracy of depression is important as both the over-diagnosis and under-diagnosis is accompanied with significant costs. Thus, continued research exploring the phenomenology and identifying effective indicators of depression in older cancer patients is needed.
PMCID: PMC4925309  PMID: 26312455
depression; cancer; assessment; psycho-oncology
4.  Peyronie’s Disease: AUA Guideline 
The Journal of urology  2015;194(3):745-753.
The purpose of this guideline is to provide a clinical framework for the diagnosis and treatment of Peyronie’s disease.
Materials and Methods
A systematic review of the literature using the PubMed®, EMBASE® and Cochrane databases (search dates 1/1/1965 to 1/26/15) was conducted to identify peer-reviewed publications relevant to the diagnosis and treatment of PD. The review yielded an evidence base of 303 articles after application of inclusion/exclusion criteria.
The systematic review was used to create guideline statements regarding treatment of PD. When sufficient evidence existed, the body of evidence for a particular treatment was assigned a strength rating of A (high quality evidence; high certainty), B (moderate quality evidence; moderate certainty), or C (low quality evidence; low certainty). Evidence-based statements of Strong, Moderate, or Conditional Recommendation were developed based on benefits and risks/burdens to patients. Additional consensus statements related to the diagnosis of PD are provided as Clinical Principles and Expert Opinions due to insufficient published evidence.
There is a continually expanding literature on PD; the Panel notes that this document constitutes a clinical strategy and is not intended to be interpreted rigidly. The most effective approach for a particular patient is best determined by the individual clinician and patient in the context of that patient’s history, values, and goals for treatment. As the science relevant to PD evolves and improves, the strategies presented here will be amended to remain consistent with the highest standards of clinical care.
PMCID: PMC5027990  PMID: 26066402
penis; fibrosis; penile induration
5.  Nonalcoholic Thiamine-Related Encephalopathy (Wernicke-Korsakoff Syndrome) Among Inpatients With Cancer: A Series of 18 Cases 
Psychosomatics  2015;57(1):71-81.
Wernicke-Korsakoff Syndrome (WKS) is a neuropsychiatric syndrome caused by thiamine deficiency. Cancer predisposes to thiamine deficiency through various mechanisms. Although many case reports exist on nonalcoholic WKS in cancer, larger qualitative studies are lacking.
Retrospective study of patients admitted to a cancer hospital and diagnosed with WKS during routine care on a psychiatric consultation service. Only patients with at least 1 additional supporting feature (magnetic resonance imaging findings, low serum thiamine concentrations, or response to treatment) were included. Data pertaining to demographics, risk factors, phenomenology, and outcomes were abstracted from medical records by chart review.
In all, 18 patients were included. All patients developed WKS during cancer treatment. Hematologic malignancy, gastrointestinal tract tumors, low oral intake, and weight loss were common risk factors. All patients presented with cognitive dysfunction, most commonly impaired alertness, attention, and short-term memory. All were diagnosed by operational criteria proposed by Caine et al., 1997 (where 2 of the following are required: nutritional deficiency, ocular signs, cerebellar signs, and either altered mental status or mild memory impairment). Few exhibited Wernicke’s classic triad. Diagnostic and treatment delay were common. Only 3 patients recovered fully.
Nonalcoholic WKS can occur during cancer treatment and manifests clinically as delirium. Diagnosis should be made using operational criteria, not Wernicke’s triad. Most patients were not underweight and had normal serum concentration of vitamin B12 and folate. A variety of mechanisms might predispose to thiamine deficiency and WKS in cancer. Given the high frequency of residual morbidity, studies should focus on decreasing diagnostic and treatment delay.
PMCID: PMC4979979  PMID: 26791514
6.  The Relationship Between Age, Anxiety, and Depression in Older Adults With Cancer 
Psycho-oncology  2014;24(6):712-717.
PMCID: PMC4320028  PMID: 25099337
Cancer; Oncology; Older Adults; Geriatric; Anxiety; Depression
7.  Psychological aspects of Peyronie’s disease 
Peyronie’s disease (PD) is an acquired fibrotic disorder (disorganized collagen deposition) in the tunica albuginea. This scar tissue or “plaque” builds up in the tunica albuginea and results in penile deformities. PD can have a significant negative impact on mood and quality of life. Although the psychological impact of PD has generally been understudied, there has been a growing body of literature that has assessed the impact PD can have on men’s mental health and relationships. The aim of this study is to review the current literature focused on the psychological and relationship impact of PD.
We performed a MEDLINE search limited to English language literature using the terms: “Peyronie’s Disease AND Psychological OR Psychosocial”. Select references were then included for review.
The research in this area confirms the clinical impressions of men with PD, which is that depression and relationship distress is prevalent. Approximately 50% of men with PD suffer from depressive symptoms and upwards of 80% report distress related to PD. It appears that these rates remain relatively stable over time. High rates of relationship stress were also reported as over 50% of men reported that PD had negatively impacted their relationship. Qualitative work in this area helps us understand the nature of this distress. Regarding body image and self-esteem, men described themselves as “abnormal”, “ugly”, “disgusting”, “like a cripple”, and a “half man”, and some of them described feelings of shame. Many men reported that they lost their sexual confidence, or ability to initiate sex with a partner, while most reported a decrease in sexual interest. Additionally, many men expressed a sense of stigmatization and isolation. This led to difficulties in speaking about their disease with sexual partners or healthcare professionals.
Taken in total, these studies indicate that those who actively treat PD should assess for distress or depressive symptoms. The standard assessment of PD could include the Peyronie’s Disease Questionnaire (PDQ), and at least two questions on individual and relationship distress, or the use of a validated questionnaire to assess depression.
PMCID: PMC4893509  PMID: 27298775
Peyronie’s disease (PD); depression; psychological; psychosocial function; sexual function
8.  TRIP13PCH-2 promotes Mad2 localization to unattached kinetochores in the spindle checkpoint response 
The Journal of Cell Biology  2015;211(3):503-516.
The ability of the conserved ATPase TRIP13PCH-2 to disassemble a Mad2-containing complex is critical to promote the spindle checkpoint response by contributing to the robust localization of Mad2 to unattached kinetochores.
The spindle checkpoint acts during cell division to prevent aneuploidy, a hallmark of cancer. During checkpoint activation, Mad1 recruits Mad2 to kinetochores to generate a signal that delays anaphase onset. Yet, whether additional factors contribute to Mad2’s kinetochore localization remains unclear. Here, we report that the conserved AAA+ ATPase TRIP13PCH-2 localizes to unattached kinetochores and is required for spindle checkpoint activation in Caenorhabditis elegans. pch-2 mutants effectively localized Mad1 to unattached kinetochores, but Mad2 recruitment was significantly reduced. Furthermore, we show that the C. elegans orthologue of the Mad2 inhibitor p31(comet)CMT-1 interacts with TRIP13PCH-2 and is required for its localization to unattached kinetochores. These factors also genetically interact, as loss of p31(comet)CMT-1 partially suppressed the requirement for TRIP13PCH-2 in Mad2 localization and spindle checkpoint signaling. These data support a model in which the ability of TRIP13PCH-2 to disassemble a p31(comet)/Mad2 complex, which has been well characterized in the context of checkpoint silencing, is also critical for spindle checkpoint activation.
PMCID: PMC4639874  PMID: 26527744
9.  Decision-Making Processes among Prostate Cancer Survivors with Rising PSA Levels: Results from a Qualitative Analysis1 
Prostate cancer survivors with a rising prostate specific antigen (PSA) level have few treatment options, experience a heightened state of uncertainty about their disease trajectory that might include the possibility of cancer metastasis and death, and often experience elevated levels of distress as they have to deal with a disease they thought they had conquered. Guided by self-regulation theory, the present study examined the cognitive and affective processes involved in shared decision making between physician and patients who experience a rising PSA after definitive treatment for prostate cancer.
In-depth interviews were conducted with 34 prostate cancer survivors who had been diagnosed with a rising PSA (i.e., biochemical failure) within the past 12 months. Survivors were asked about their experiences and affective responses after being diagnosed with a rising PSA and while weighing potential treatment options. In addition, patients were asked about their decision-making process for the initial prostate cancer treatment.
Compared to the initial diagnosis, survivors with a rising PSA reported increased negative affect following their diagnosis, concern about the treatability of their disease, increased planning and health behavior change, heightened levels of worry preceding doctor’s appointments (especially prior to the discussion of PSA testing results), and a strong reliance on physicians’ treatment recommendations.
Prostate cancer survivors’ decision-making processes for the treatment of a rising PSA are markedly different from those of the initial diagnosis of prostate cancer. Because patients experience heightened distress and rely more heavily on their physicians’ recommendations with a rising PSA, interactions with the health care provider provide an excellent opportunity to address and assist patients with managing the uncertainty and distress inherent with rising PSA levels.
PMCID: PMC4424110  PMID: 25385751
10.  Spindle assembly checkpoint proteins regulate and monitor meiotic synapsis in C. elegans 
The Journal of Cell Biology  2015;211(2):233-242.
In C. elegans, a meiotic checkpoint monitors synapsis between homologous chromosomes. Mad1, Mad2, and Bub3 are required for this checkpoint and negatively regulate synapsis, suggesting a possible role for these proteins in monitoring the stability of homologue pairing.
Homologue synapsis is required for meiotic chromosome segregation, but how synapsis is initiated between chromosomes is poorly understood. In Caenorhabditis elegans, synapsis and a checkpoint that monitors synapsis depend on pairing centers (PCs), cis-acting loci that interact with nuclear envelope proteins, such as SUN-1, to access cytoplasmic microtubules. Here, we report that spindle assembly checkpoint (SAC) components MAD-1, MAD-2, and BUB-3 are required to negatively regulate synapsis and promote the synapsis checkpoint response. Both of these roles are independent of a conserved component of the anaphase-promoting complex, indicating a unique role for these proteins in meiotic prophase. MAD-1 and MAD-2 localize to the periphery of meiotic nuclei and interact with SUN-1, suggesting a role at PCs. Consistent with this idea, MAD-1 and BUB-3 require full PC function to inhibit synapsis. We propose that SAC proteins monitor the stability of pairing, or tension, between homologues to regulate synapsis and elicit a checkpoint response.
PMCID: PMC4621841  PMID: 26483555
11.  Assessment of Penile Vibratory Stimulation as a Management Strategy in Men with Secondary Retarded Orgasm 
Urology  2007;69(3):552-556.
To evaluate the effectiveness of penile vibratory stimulation for the management of retarded orgasm. Retarded orgasm, a condition characterized by difficulty achieving orgasm and ejaculation, is one of the most recalcitrant of the male sexual dysfunctions. Currently, no evidence-based treatments have been proven to ameliorate this condition.
Men who had a complete inability to achieve an orgasm during sexual relations in the previous 3 months were instructed in the use of penile vibratory stimulation. The men’s responses were measured by self-report of orgasm function and using the orgasm and satisfaction domains of the International Index of Erectile Function. The responses were assessed at baseline (admission into the study) and at 3 and 6 months.
A total of 36 men met the inclusion criteria, and 72% reported the restoration of orgasm. These responders reported that orgasm during sexual relations occurred 62% of the time. A statistically and clinically significant increase occurred in the orgasm and satisfaction domains of the International Index of Erectile Function between the baseline visit and the 3-month follow-up visit. These gains were sustained at 6 months.
Penile vibratory stimulation is an effective treatment for retarded orgasm. Penile vibratory stimulation should be integrated into current cognitive-behavioral sex therapy techniques to achieve maximal effectiveness and satisfaction.
PMCID: PMC4765806  PMID: 17382163
12.  Back to Baseline: Erectile Function Recovery after Radical Prostatectomy from the Patients’ Perspective 
The journal of sexual medicine  2013;10(6):1636-1643.
A variety of erectile function recovery (EFR) rates are reported post radical prostatectomy (RP), with some suggesting EFR rates over 90% [1]. Clinical experience suggests that patients view EFR as getting back to their baseline (BTB) erectile functioning (EF) without the use of medication.
This study explores EFR defined as BTB.
Men pre-RP and 24 months post-RP completed the Erectile Function Domain (EFD) of the International Index of Erectile Function and one question on phosphodiesterase type 5 inhibitor (PDE5i) use. Men using a PDE5i at baseline were excluded.
Main Outcome Measures
At 24 m, “back to baseline” was defined as achieving the baseline EFD score (within 1 point or higher). Analyses included descriptive statistics, chi-square, and logistic regression.
One hundred eighty men had an average age at RP of 59 (SD = 7) years. When including men who were using a PDE5i at 24 months, 43% (N = 78, 95% CI: 36–51%) returned BTB. When considering BTB without the use of a PDE5i, 22% (N = 39, 95% CI: 16% to 28%) returned BTB. When focusing on a subset of men with baseline EFD ≥ 24 (N = 132), 36% (N = 47, 95% CI: 28% to 44%) returned BTB at 24 months using a PDE5i and 16% (N = 21, 95% CI: 11% to 23%) without the use of aPDE5i. For this group, there was a significant difference by age (<60 years, 23% vs. ≥60 years, 4%, P< 0.001), which remained a significant predictor (OR = 6.25, 95% CI: 1.88 to 50, P< 0.001) in multivariable analysis.
Twenty-two percent of the entire sample and 16% of the men with functional (EFD ≥ 24) baseline erections returned to BTB EF without the use of medication. Only 4% of men who were ≥60 years old with functional erections pre-surgery achieved BTB EF. Although gaining partial EF is also important, men pre-RP should be educated on EFR and the chance of “back to baseline” EF.
PMCID: PMC4742368  PMID: 23551767
Prostate Cancer; Erectile Dysfunction; Sexual Function; Pre-operative Erectile Function
13.  Medical Help-Seeking for Sexual Concerns in Prostate Cancer Survivors 
Sexual Medicine  2016;4(1):e7-e17.
Although sexual dysfunction is common after prostate cancer, men's decisions to seek help for sexual concerns are not well understood.
Describe predictors of actual prior help-seeking and intended future medical help-seeking for sexual dysfunction in prostate cancer survivors.
A cross-sectional survey of 510 prostate cancer survivors assessed masculine beliefs, attitudes, support/approval from partner/peer networks (subjective norm), and perceived control as predictors of medical help-seeking for sexual concerns. A theory of planned behavior (TPB) perspective was used to examine actual prior and planned future behavior and contributing factors. Statistical analyses included multiple and logistic regressions.
Main Outcome Measures
Intention to see a doctor for sexual advice or help in the next 6 months was measured using the intention subscale adapted from the Attitudes to Seeking Help after Cancer Scale. Prior help-seeking was measured with a dichotomous yes/no scale created for the study.
Men were Mage 71.69 years (SD = 7.71); 7.54 years (SD = 4.68) post-diagnosis; received treatment(s) (58.1% radical prostatectomy; 47.1% radiation therapy; 29.4% hormonal ablation); 81.4% reported severe ED (IIED 0–6) and 18.6% moderate–mild ED (IIED 7–24). Overall, 30% had sought sexual help in the past 6 months, and 24% intended to seek help in the following 6 months. Prior help-seeking was less frequent among men with severe ED. Sexual help-seeking intentions were associated with lower education, prior sexual help-seeking, sexual importance/ priority, emotional self-reliance, positive attitude, and subjective norm (R2 = 0.56).
The TPB has utility as a theoretical framework to understand prostate cancer survivors' sexual help-seeking decisions and may inform development of more effective interventions. Masculine beliefs were highly salient. Men who were more emotionally self-reliant and attributed greater importance to sex formed stronger help-seeking intentions. Subjective norm contributed most strongly to help-seeking intentions suggesting that health professionals/partners/peers have a key role as support mechanisms and components of psycho-sexual interventions.
PMCID: PMC4822483  PMID: 26796856
Prostate Cancer; Sexual Help-Seeking; Erectile Dysfunction
15.  The Greater Affinity of JC Polyomavirus Capsid for α2,6-Linked Lactoseries Tetrasaccharide c than for Other Sialylated Glycans Is a Major Determinant of Infectivity 
Journal of Virology  2015;89(12):6364-6375.
The human JC polyomavirus (JCPyV) establishes an asymptomatic, persistent infection in the kidneys of the majority of the population and is the causative agent of the fatal demyelinating disease progressive multifocal leukoencephalopathy (PML) in immunosuppressed individuals. The Mad-1 strain of JCPyV, a brain isolate, was shown earlier to require α2,6-linked sialic acid on the lactoseries tetrasaccharide c (LSTc) glycan for attachment to host cells. In contrast, a JCPyV kidney isolate type 3 strain, WT3, has been reported to interact with sialic acid-containing gangliosides, but the role of these glycans in JCPyV infection has remained unclear. To help rationalize these findings and probe the effects of strain-specific differences on receptor binding, we performed a comprehensive analysis of the glycan receptor specificities of these two representative JCPyV strains using high-resolution X-ray crystallography and nuclear magnetic resonance (NMR) spectroscopy, and correlated these data with the results of infectivity assays. We show here that capsid proteins of Mad-1 and WT3 JCPyV can both engage LSTc as well as multiple sialylated gangliosides. However, the binding affinities exhibit subtle differences, with the highest affinity observed for LSTc. Engagement of LSTc is a prerequisite for functional receptor engagement, while the more weakly binding gangliosides are not required for productive infection. Our findings highlight the complexity of virus-carbohydrate interactions and demonstrate that subtle differences in binding affinities, rather than the binding event alone, help determine tissue tropism and viral pathogenesis.
IMPORTANCE Viral infection is initiated by attachment to receptors on host cells, and this event plays an important role in viral disease. We investigated the receptor-binding properties of human JC polyomavirus (JCPyV), a virus that resides in the kidneys of the majority of the population and can cause the fatal demyelinating disease progressive multifocal leukoencephalopathy (PML) in the brains of immunosuppressed individuals. JCPyV has been reported to interact with multiple carbohydrate receptors, and we sought to clarify how the interactions between JCPyV and cellular carbohydrate receptors influenced infection. Here we demonstrate that JCPyV can engage numerous sialylated carbohydrate receptors. However, the virus displays preferential binding to LSTc, and only LSTc mediates a productive infection. Our findings demonstrate that subtle differences in binding affinity, rather than receptor engagement alone, are a key determinant of viral infection.
PMCID: PMC4474300  PMID: 25855729
16.  Modulation of a Pore in the Capsid of JC Polyomavirus Reduces Infectivity and Prevents Exposure of the Minor Capsid Proteins 
Journal of Virology  2015;89(7):3910-3921.
JC polyomavirus (JCPyV) infection of immunocompromised individuals results in the fatal demyelinating disease progressive multifocal leukoencephalopathy (PML). The viral capsid of JCPyV is composed primarily of the major capsid protein virus protein 1 (VP1), and pentameric arrangement of VP1 monomers results in the formation of a pore at the 5-fold axis of symmetry. While the presence of this pore is conserved among polyomaviruses, its functional role in infection or assembly is unknown. Here, we investigate the role of the 5-fold pore in assembly and infection of JCPyV by generating a panel of mutant viruses containing amino acid substitutions of the residues lining this pore. Multicycle growth assays demonstrated that the fitness of all mutants was reduced compared to that of the wild-type virus. Bacterial expression of VP1 pentamers containing substitutions to residues lining the 5-fold pore did not affect pentamer assembly or prevent association with the VP2 minor capsid protein. The X-ray crystal structures of selected pore mutants contained subtle changes to the 5-fold pore, and no other changes to VP1 were observed. Pore mutant pseudoviruses were not deficient in assembly, packaging of the minor capsid proteins, or binding to cells or in transport to the host cell endoplasmic reticulum. Instead, these mutant viruses were unable to expose VP2 upon arrival to the endoplasmic reticulum, a step that is critical for infection. This study demonstrated that the 5-fold pore is an important structural feature of JCPyV and that minor modifications to this structure have significant impacts on infectious entry.
IMPORTANCE JCPyV is an important human pathogen that causes a severe neurological disease in immunocompromised individuals. While the high-resolution X-ray structure of the major capsid protein of JCPyV has been solved, the importance of a major structural feature of the capsid, the 5-fold pore, remains poorly understood. This pore is conserved across polyomaviruses and suggests either that these viruses have limited structural plasticity in this region or that this pore is important in infection or assembly. Using a structure-guided mutational approach, we showed that modulation of this pore severely inhibits JCPyV infection. These mutants do not appear deficient in assembly or early steps in infectious entry and are instead reduced in their ability to expose a minor capsid protein in the host cell endoplasmic reticulum. Our work demonstrates that the 5-fold pore is an important structural feature for JCPyV.
PMCID: PMC4403419  PMID: 25609820
17.  Structural Optimization of a Retrograde Trafficking Inhibitor that Protects Cells from Infections by Human Polyoma- and Papillomaviruses 
Bioorganic & medicinal chemistry  2014;22(17):4836-4847.
Human polyoma- and papillomaviruses are non-enveloped DNA viruses that cause severe pathologies and mortalities. Under circumstances of immunosuppression, JC polyomavirus causes a fatal demyelinating disease called progressive multifocal leukoencephalopathy (PML) and the BK polyomavirus is the etiological agent of polyomavirus-induced nephropathy and hemorrhagic cystitis. Human papillomavirus type 16, another non-enveloped DNA virus, is associated with the development of cancers in tissues like the uterine cervix and oropharynx. Currently, there are no approved drugs or vaccines to treat or prevent polyomavirus infections. We recently discovered that the small molecule Retro-2cycl, an inhibitor of host retrograde trafficking, blocked infection by several human and monkey polyomaviruses. Here, we report diversity-oriented syntheses of Retro-2cycl and evaluation of the resulting analogs using an assay of human cell infections by JC polyomavirus. We defined structure-activity relationships and also discovered analogs with significantly improved potency as suppressors of human polyoma- and papillomavirus infection in vitro. Our findings represent an advance in the development of drug candidates that can broadly protect humans from non-enveloped DNA viruses and toxins that exploit retrograde trafficking as a means for cell entry.
PMCID: PMC4378546  PMID: 25087050
Polyomavirus; Papillomavirus; Retrograde Trafficking; Dihydroquinazolinone; SAR
18.  Couples-based interventions following prostate cancer treatment: a narrative review 
Sexual dysfunction following prostate cancer (PC) treatment often results in sexual avoidance and a loss of sexual intimacy, which can lead to relationship distress. This review aims to evaluate six studies intended to address relational and sexual intimacy following PC treatment and discuss methodological concerns which may help produce more effective interventions.
Electronic databases used to conduct literature searches included Medline, PsychINFO, and Web of Science. Studies were included if they were: randomized controlled trials (RCTs) using samples of men diagnosed with PC of any stage, had a psychosocial intervention, and addressed at least one sexual and relational outcome.
As a whole, the literature has produced mixed results. While significant findings were reported, many of the primary hypotheses were not achieved. The six studies show that men with PC may benefit from education and support related to treatment options for erectile dysfunction (ED), whereas their partners may benefit more from interventions focused on relational issues. Important methodological limitations included: selection of general outcome measures as opposed to measures specific to sexuality or intimacy outcomes, lack of assessing distress or bother of the patient/couples as study entry criteria, heterogeneity of study populations, and lack of innovative intervention content as the current studies tested standard educational interventions, sex therapies techniques, and couples therapy strategies with only marginal success.
Interventions based on innovative theoretical approaches as well as study designs that address the outlined methodological limitations are needed in this area.
PMCID: PMC4708124  PMID: 26813683
Prostate cancer (PC); erectile dysfunction (ED); sexual function; erectile rehabilitation
19.  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
20.  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
21.  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
23.  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
24.  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
25.  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

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