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Pharmaceutical proteins, compared to small molecular weight drugs, are relatively fragile molecules, thus necessitating monitoring protein unfolding and aggregation during production and post-marketing. Currently, many analytical techniques take offline measurements, which cannot directly assess protein folding during production and unfolding during processing and storage. In addition, several orthogonal techniques are needed during production and market surveillance. In this study, we introduce the use of time-gated Raman spectroscopy to identify molecular descriptors of protein unfolding. Raman spectroscopy can measure the unfolding of proteins in-line and in real-time without labels. Using K-means clustering and PCA analysis, we could correlate local unfolding events with traditional analytical methods. This is the first step toward predictive modeling of unfolding events of proteins during production and storage.

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Targeting cytotoxic 4ß-phorbol esters toward cancer tissue was attempted by conjugating a 4ß-pborbol derivative with substrates for the proteases prostate-specific antigen (PSA) and prostate-specific membrane antigen (PSMA) expressed in cancer tissue. The hydrophilic peptide moiety was hypothesized to prevent penetration of the prodrugs into cells and prevent interaction with PKC. Cleavage of the peptide in cancer tumors was envisioned to release lipophilic cytotoxins, which subsequently penetrate into cancer cells. The 4ß-phorbol esters were prepared from 4ß-phorbol isolated from Croton tiglium seeds, while the peptides were prepared by solid-phase synthesis. Cellular assays revealed activation of PKC by the prodrugs and efficient killing of both peptidase positive as well as peptidase negative cells. Consequently no selectivity for enzyme expressing cells was found.

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INTRODUCTION AND HYPOTHESIS: The aim of this study was to report long-term subjective and objective outcomes after the transvaginal mesh (TVM) procedure in long-term. Possible late-onset complications were of particular interest. METHODS: This was a retrospective analysis of TVM performed using Prolift™ transvaginal mesh measuring subjective outcome using validated questionnaires. Objective outcome was assessed using the Pelvic Organ Prolapse Quantification (POP-Q) system using two definitions: POP-Q stage ≤ 1, and vaginal wall prolapse at or above the hymen or vaginal apex not descending below the upper third of the vagina. Complications were reported with the Prosthesis/Graft Complication Classification Code designed by the International Continence Society/International Urogynecological Association (ICS/IUGA). RESULTS: Of 195 patients, 161 (82.6 %) participated this study after a median of 7 years. The scores in questionnaires evaluating urinary (UI) or anal incontinence and constipation or pelvic floor symptoms were low, indicating favorable surgical outcomes. Altogether, 80.1 % of patients were satisfied with the procedure. Anatomical cure was 56.4 % and 69.3 % depending on the definition used. Reoperation due to POP in any compartment was performed in 16.2 % of patients. Mesh exposure rate was 23 %, most of these being asymptomatic and of late onset. CONCLUSIONS: Outcome of the TVM procedure was satisfactory. Anatomical cure was inferior to subjective cure. Mesh exposure rate was high; most exposures observed in the long-term were of late onset and were asymptomatic.

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STUDY OBJECTIVE: To report the subjective and objective outcomes and patient satisfaction with the outside-in transobturator tape (TOT) procedure during long-term follow-up. DESIGN: Clinical follow-up study (Canadian Task Force classification II-2). SETTING: University hospital. PATIENTS: One hundred ninety-one women who underwent the TOT procedure. Of these, 66% had stress urinary incontinence and 34% had mixed urinary incontinence, and 45% underwent concomitant surgery. INTERVENTIONS: Patients underwent surgery between May 2003 and December 2004 using the TOT procedure. After a mean follow-up of 6.5 years, postal questionnaires and an invitation for a follow-up visit to the outpatient clinic were sent to the patients. Objective cure was defined as a negative result of a stress test and no repeat operation because of stress urinary incontinence during follow-up. Subjective outcome was evaluated using the following validated questionnaires: UISS (Urinary Incontinence Severity Score), DIS (Detrussor Instability Score), VAS (visual analog scale, 0-100), short versions of the IIQ-7 (Incontinence Impact Questionnaire-7) and UDI-6 (Urogenital Distress Inventory-6), and the EQ-5D and EQ-5D VAS. Patient satisfaction was evaluated using a self-tailored questionnaire. MEASUREMENTS AND MAIN RESULTS: Of 191 patients, 139 (73%) were evaluated after a mean follow-up of 6.5 years. Objective and subjective cure rates were 89% and 83%, respectively. Of the patients with genuine stress urinary incontinence, 92% were completely or quite satisfied with the surgery, and 76% of the patients with mixed urinary incontinence were satisfied (p < .001). Patients with body mass index >30 had significantly higher scores on the IIQ-7, UDI-6 (p < .01 for both), VAS (p < .001), UISS (p < .01), and DIS (p < .001), thus indicating a less favorable outcome of the procedure. CONCLUSION: A high objective cure rate persisted after a mean follow-up of 6.5 years. Caution is advised when the TOT procedure is planned in patients with mixed urinary incontinence or severe obesity.

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OBJECTIVES: To evaluate the long-term outcome of the tension-free vaginal tape procedure. METHODS: A total of 191 patients were operated on with tension-free vaginal tape between January 1998 and May 2000. Of these, 127 (66%) had stress urinary incontinence, 64 (34%) had mixed urinary incontinence and 39 (20%) had recurrent incontinence. A total of 34 (18%) patients had had concomitant surgery. The diagnosis of incontinence was based on a history of leakage during stress and physical examination with a supine stress test in all patients. Tension-free vaginal tape was carried out under local (82%) or spinal (18%) anesthesia. After a mean of 10.5 years follow up, the assessment included a gynecological examination and a supine stress test. Subjective outcome was evaluated with Urinary Incontinence Severity Score, Detrusor Instability Score, visual analog scale, European quality of life-five dimensions, European quality of life - visual analog scale and short versions of Incontinence Impact Questionnaire-7 and Urogenital Distress Inventory-6. Objective cure was defined as a negative stress test and an absence of reoperation for incontinence during the follow up. RESULTS: A total of 138 (72%) of 191 patients were evaluated. Patients with minimally invasive surgery before operation had significantly higher scores in Urinary Incontinence Severity Score, Detrusor Instability Score, Incontinence Impact Questionnaire-7 and Urogenital Distress Inventory-6 at follow up than the patients with stress urinary incontinence (P < 0.01). Recurrent incontinence and concomitant surgery did not affect the long-term outcome. Three patients (2.3%) had late-onset adverse events. The objective and subjective cure rates were 90% and 78%, respectively. CONCLUSIONS: The tension-free vaginal tape procedure is effective and safe even after 10 years. The objective cure rate is high, but the subjective outcome is significantly lower in mixed urinary incontinence patients compared with patients with pure stress urinary incontinence. Recurrent stress urinary incontinence does not affect the outcome, and tape-related problems are rare.

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