Synergistic effects of nelfinavir and bortezomib on proteotoxic death of NSCLC and multiple myeloma cells.

Exploiting protein homeostasis is a new therapeutic approach in cancer. Nelfinavir (NFV) is an HIV protease inhibitor that induces endoplasmic reticulum (ER) stress in cancer cells. Under conditions of ER stress, misfolded proteins are transported from the ER back to the cytosol for subsequent degradation by the ubiquitin-proteasome system. Bortezomib (BZ) is a proteasome inhibitor and interferes with degradation of misfolded proteins. Here, we show that NFV and BZ enhance proteotoxicity in non-small cell lung cancer (NSCLC) and multiple myeloma (MM) cells. The combination synergistically inhibited cell proliferation and induced cell death. Activating transcription factor (ATF)3 and CCAAT-enhancer binding protein homologous protein (CHOP), markers of ER stress, were rapidly increased, and their siRNA-mediated knockdown inhibited cell death. Knockdown of double-stranded RNA activated protein kinase-like ER kinase, a signal transducer in ER stress, significantly decreased apoptosis. Pretreatment with the protein synthesis inhibitor, cycloheximide, decreased levels of ubiquitinated proteins, ATF3, CHOP, and the overall total cell death, suggesting that inhibition of protein synthesis increases cell survival by relieving proteotoxic stress. The NFV/BZ combination inhibited the growth of NSCLC xenografts, which correlated with the induction of markers of ER stress and apoptosis. Collectively, these data show that NFV and BZ enhance proteotoxicity in NSCLC and MM cells, and suggest that this combination could tip the precarious balance of protein homeostasis in cancer cells for therapeutic gain.

Ceramide mediates nanovesicle shedding and cell death in response to phosphatidylinositol ether lipid analogs and perifosine.

Anticancer phospholipids that inhibit Akt such as the alkylphospholipid perifosine (Per) and phosphatidylinositol ether lipid analogs (PIAs) promote cellular detachment and apoptosis and have a similar cytotoxicity profile against cancer cell lines in the NCI60 panel. While investigating the mechanism of Akt inhibition, we found that short-term incubation with these compounds induced rapid shedding of cellular nanovesicles containing EGFR, IGFR and p-Akt that occurred in vitro and in vivo, while prolonged incubation led to cell detachment and death that depended on sphingomyelinase-mediated generation of ceramide. Pretreatment with sphingomyelinase inhibitors blocked ceramide generation, decreases in phospho-Akt, nanovesicle release and cell detachment in response to alkylphospholipids and PIAs in non-small cell lung cancer cell lines. Similarly, exogenous ceramide also decreased active Akt and induced nanovesicle release. Knockdown of neutral sphingomyelinase decreased, whereas overexpression of neutral or acid sphingomyelinase increased cell detachment and death in response to the compounds. When transferred in vitro, PIA or Per-induced nanovesicles increased ceramide levels and death in recipient cells. These results indicate ceramide generation underlies the Akt inhibition and cytotoxicity of this group of agents, and suggests nanovesicle shedding and uptake might potentially propagate their cytotoxicity in vivo.

A study on the mechanical reliability of the Dacomed snap gauge: implications for the differentiation between organic and psychogenic impotence.

Two experiments were conducted testing reliability of expansion chamber determined gauge element breakage ranges; 20 trials with sexually functional males provided comparative data on the gauge in actual application. Circumference of the expansion chamber and increases in penile circumference were simultaneously monitored via a mercury strain gauge. Results for both experiments indicated considerable overlap at gauge element breakpoints, and yielded an overall misdiagnosis rate of 15.5% in a young, healthy population.

Counseling and therapy for sexual problems in the elderly.

The case of Bill and Emily dramatically illustrates that stereotypes about aging and sexuality can be very wrong and can negatively influence how elderly patients both think and act sexually. These stereotypes can also lead to gross errors in clinical management of the sexual concerns of elderly patients and to treatment of the elderly with less than humanistic concerns for their sexual needs. It is to be hoped that in the future, helping professionals will consider sexuality as a priority in their work with elderly patients.

Clinical follow-up of couples treated for sexual dysfunction.

The present status of 38 couples who had been treated at a clinic for sexual dysfunction 3 years previously was determined by a self-report assessment battery. The battery consisted of the Sexual Interaction Inventory, the Locke-Wallace Marriage Inventory, and the Sexual History Form completed at pretreatment, immediately posttreatment, 3 months after treatment, and at 3-year follow-up. An additional Follow-up Questionnaire was completed at the 3-year point only. At 3-year follow-up, analysis of data by diagnostic category indicated that sexual desire dysfunction for both men and women was particularly resistant to sustained behavioral change. Men with erectile difficulty reported significant improvement in their ability to maintain erections during intercourse but not in their ability to achieve erections prior to intercourse. Data from men with premature ejaculation revealed some immediate significant posttherapy gains, which, with the exception of length of foreplay, were not sustained at 3-year follow-up. For women with global inorgasmia, a significant increase in orgasmic response was reported. Data from women with situational orgasmic difficulties indicated some success in improving frequency of orgasm through masturbation and through genital caress; however, these changes did not reach statistical significance. Across all diagnostic categories, both men and women respondents reported increased satisfaction in their sexual relationship. Satisfaction in the marital relationship showed a more varied response pattern.

Diagnosis and treatment of male sexual dysfunction.

This paper presents a critical review of recent work on diagnosis and treatment of male sexual dysfunction. One recent advance has been a focus on low sexual desire in males. Hormonal disorders are relatively uncommon in such men, with family-of-origin and couple-dynamic issues usually cited in the clinical literature as major etiologic factors. Recent work on erectile failure has focused on differential diagnosis of physiological and psychological factors in erectile failure. To date, no simple differential diagnostic procedure has been identified, and a complex and expensive multidimensional evaluation is required for accurate diagnosis. Treatment for premature ejaculation continues to be very effective, but an understanding of the mechanism underlying treatment effectiveness has remained elusive. The cause of inhibited ejaculation also continues to be unclear, although medication side effects have been recognized as a common contributing factor. Across all the male dysfunctions, clinical reports have outweighed empirical studies in the recent literature. Heterogeneity of patient groups, lack of objective outcome measures, lack of control groups, and other basic methodological problems, continue to plague this area of research.

Three-year follow-up of couples evaluated for sexual dysfunction.

The present status of 49 couples who three years previously had been evaluated but not treated at a clinic for sexual dysfunction was determined by a self-report assessment battery. The battery consisted of the Sexual Interaction Inventory, the Locke-Wallace Marriage Inventory and the Sexual History Form completed at initial evaluation and follow-up. An additional Follow-up Questionnaire was completed at post only. Approximately 52% of the men and 54% of the women reported receiving therapy during the period between initial intake and follow-up. Analysis of male data revealed that with the exceptions of estimates of mate satisfaction and marital happiness, all other variables measuring sexual behaviors and attitudes did not show significant changes over time. Men who received subsequent therapy reported significantly more erectile difficulty at both intake and follow-up than their nontreated counterparts. In contrast, women showed significant improvement over time in sexual satisfaction, acceptance of mate, and ability to achieve orgasm through a wider variety of means. These improvements were reported by women who had therapy during the interim period as well as women who had not had therapy. Repeated measured ANOVAs and t-test analyses were performed examining the effects of male dysfunction on female functioning. Interpretations of the differences in change noted over time between women and men are offered as well as suggestions for future research.

Clinical outcome of sex therapy. Effects of daily v weekly treatment.

The effectiveness of sex therapy has been questioned recently. The present outcome study of 69 lower-middle-class couples, who were not highly selected with respect to severity of personal and marital distress, used standardized instruments to measure change over five time periods: intake, history, posttherapy, three-month, and one-year follow-up. Using an own-control design, a 15-session weekly treatment was compared with a 15-session daily treatment. Overall, treatment was successful in improving sexual and marital satisfaction as well as specific symptom remission; there was little decline at the three-month and one-year follow-ups. The least symptomatic improvement occurred for erectile problems and female secondary inorgasmic dysfunction, and there was some suggestion of a gradual nonsignificant decline of overall sexual and marital satisfaction at follow-up. The outcome of daily v weekly treatment was generally not different, with only some indication of better results for secondary inorgasmia and erectile failure when treated in the weekly mode.

Multiaxial problem-oriented system for sexual dysfunctions: an alternative to DSM-III.

In a multiaxial system for classifying the sexual dysfunctions, the axes specify sexual problems associated with the desire, arousal, and orgasm phases of the sexual response cycle, as well as types of coital pain, dissatisfaction with the frequency of sex, and certain other information relevant to sexual functioning. In contrast to DSM-III and other existing diagnostic systems for sexual dysfunctions, this new multiaxial system is based on highly specific empirical descriptions of sexual behavior. There are no inferences made about the cause of the dysfunctions.

Treatment effectiveness for dysfunctions of sexual desire.

Archival data from the Sex Therapy Center at Stony Brook were analyzed to determine the prevalence of desire phase sexual dysfunctions and the effectiveness of treating them with behavioral sex therapy. When cases were rediagnosed with a multi-axial problem-oriented system, increases from 1974-1981 in both the prevalence of desire phase problems and of male low sexual desire were observed. Data suggested that wives display more extreme patterns of sexual avoidance than do husbands in couples seeking sex therapy. Outcome statistics on marital adjustment, overall sexual satisfaction, the frequency of intercourse and masturbation, and patterns of initiation of sexual activity reveal significant positive changes after treatment. These changes are not due to nonspecific factors and are maintained at follow-up. Sex therapy was equally successful for male-centered vs. female-centered problems, for low sexual desire vs. aversion to sex, and for global or lifelong dysfunctions vs. the more recent or situational ones. Posttreatment gains reflect a minimally adequate sexual relationship, however, rather than an optimal degree of intimacy and pleasure.

Assessing sexual behavior in couples.

The role of formal assessment in the practice of sex therapy with couples is discussed. A case is made for the use of behaviorally oriented paper-and-pencil tests of the self-report variety, in clinical settings, at two points in time: prior to any therapist-client contact and following completion of therapy. Such procedures are both efficient and effective, yielding information relevant to diagnosis, treatment planning, and development of clinical skills. Assessment procedures used routinely at the Stony Brook Sex Therapy Center are described and illustrated using sample cases. The authors suggest that behavioral assessment approaches have considerable clinical potential which has yet to be fully realized.

Secondary orgasmic dysfunction. I. Analysis and strategies for treatment.

Following treatment of six cases of primary orgasmic dysfunction and six cases of secondary orgasmic dysfunction, an analysis of assessment and outcome data indicated that (1)clients with secondary orgasmic dysfunction and those with primary orgasmic dysfunction did not differ significantly in most aspects of sexual behavior before treatment; (2) before treatment, secondary orgasmic dysfunction tended to be associated with a disturbed marital relationship, while primary orgasmic dysfunction did not; (3) following a behavioral treatment program focused on anxiety reduction and sexual skill training, organism in coitus was attained by clients with primary orgasmic dysfunction but not by clients with secondary orgasmic dysfunction. Based on these findings, suggestions for effective treatment of secondary orgasmic dysfunction are made.

Secondary orgasmic dysfunction. II. Case study.

The treatment of a case of secondary orgasmic dysfunction is described. In this case, a direct behavioral retraining program was employed to increase the couple's repertoire of effective sexual behaviors. An extinction and successive approximation procedure was used to transfer ortasmic responsiveness from solitary masturbation to heterosexual coitus. Since other data have indicated that nonsexual marriage problems contribute to the maintenance of secondary orgasmic dysfunction, a direct, confrontive intervention into the marital relationship was made concurrent with the sexual retraining program. Outcome data are presented to illustrate the effectiveness of the reatment procedures.