Search

Dipeptidyl peptidase 4 inhibitors (DPP4is), commonly used drugs for treatment of type 2 diabetes, increase the risk for bullous pemphigoid (BP). Currently, the mechanism leading to the loss of immunological tolerance of the cutaneous adhesion molecule BP180 as well as similarities and differences in disease progression between DPP4i-associated BP (DPP4i-BP) and DPP4i-independent regular BP are largely unknown. We analyzed the expression of 32 cytokines and two proteases by Luminex and ELISA assays in samples taken from lesional and nonlesional skin of patients with regular BP or DPP4i-BP and healthy controls. Cytokines mediating B-cell survival and targeting such as BAFF, CCL4, CXCL12, and IL-6 were expressed at a higher level in the lesional regular BP skin than the levels in the lesional DPP4i-BP skin. The DPP4i-BP samples had increased levels of eosinophilic cytokines CCL1, CCL17, CCL26, and IL-5, which correlated with the serum level of anti-BP180 NC16A IgG autoantibodies. The mRNA expression of BAFF, IL6, CCL1, CCL17, CCL26, and IL5 measured by qPCR correlated with the protein levels. Taken together, the cutaneous cytokine profiles were found to provide distinctive molecular fingerprints between regular BP and DPP4i-BP., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Estramustine phosphate (EMP) and estramustine binding protein antibody (EMBP-AB) accumulate in the mouse prostate. The distribution of radioiodinated EMBP-AB in tumor mice was investigated to assess its therapeutic potential against prostate cancer., Materials and Methods: Mice with DU-145 prostate cancer xenografts received 243 microCi of I-125-labeled EMBP-AB (RI-EMBP-AB). The concentration of activity in different organs was measured 4 h after the injection., Results: The blood contained 0.45% of the injected dose per gram, the prostate 2.4%, the testes 0.95% and the tumor 0.65%. Radioactivity in these organs decreased more rapidly than in other organs. The doses of radiation absorbed by the prostate and the tumor, assuming a 1 mCi injected dose, were 1.81 and 0.92 cGy, respectively., Conclusion: Most other organs would receive relatively high doses of radioactivity, were I-125 to be used in therapeutic doses. Therefore, RI-EMBP-AB is not beneficial in radionuclide treatment as compared to possible EMP applications.

Background: Estramustine is an anti-mitotic cytostatic drug that also enhances the effect of radiotherapy. The mechanism of radiosensitization is not thoroughly known. Since both radiotherapy and estramustine induce apoptosis in prostate cancer cells, we conducted an experiment to show whether radiosensitization is mediated by apoptosis., Materials and Methods: DU-145 human prostate cancer cells were xenografted to nude mice and treated with estramustine for 2 weeks and external radiation for 3 to 6 days (18 to 36 Gy). Tumor regression was measured mechanically and the rate of apoptosis defined by the amount of low molecular weight DNA fragmentation. Follow-up time was 1 to 18 days., Results: The tumor size regressed in the group of mice receiving both radiotherapy and estramustine. Four weeks after the treatment, apoptosis was accentuated in the tumors treated with estramustine or radiation but not with their combination., Conclusion: Estramustine potentiates radiotherapy, but not by enhancing radiation-induced apoptosis.

Purpose: Early diagnosis of prostate cancer is a necessary, but not sufficient, prerequisite for an effective screening program aiming at mortality reduction. We compared tumor characteristics between the screening and control arms in the Finnish population-based screening trial., Experimental Design: The Finnish trial is the largest component in the European Randomized Study of Screening for Prostate Cancer. A total of 24,000 men aged 55-67 years were randomized to the screening arm, whereas 35,973 men formed the control arm during the first three screening years. At the time of invitation, 22,732 men were eligible for screening, and 15,685 (69%) participated. A prostate-specific antigen (PSA) concentration of > or ==" BORDER="0">4 micro g/liter was defined as a screening-positive finding., Results: The detection rate among screenees was 2.4% (377 of 15,685), whereas 0.6% (40 of 7,047) of nonparticipants in the screening arm and 0.3% (112 of 35,973) of the controls were diagnosed with prostate cancer during the first postrandomization year in the absence of screening. In the screening arm, 82% of the cancers were clinically organ confined compared with 65% in the control arm. Yet, both the absolute number and cumulative incidence of advanced cancer were higher in the screening arm. No differences were seen in the WHO grade distribution between the study groups. The median PSA was substantially lower among screen-detected cases (7.1 micro g/liter) than among nonattenders (15.7 micro g/liter) and controls (13.2 micro g/liter)., Conclusions: Our findings on intermediate indicators of PSA screening provide encouraging, yet inconclusive evidence for eventual mortality reduction.

Objective: Lead-time in prostate cancer screening was estimated using data from the Finnish randomized, population-based trial., Methods: Lead-time was defined as the duration of follow-up needed to accrue the same expected number of incident prostate cancer cases in the absence of screening as detected in the initial screening round. Expected numbers were calculated using an age-cohort model., Results: Based on findings among 10,000 men screened in 1996-1997 with 292 screen-detected cancers, lead-time was estimated as approximately 5-7 years, depending on the reference rates used. This corresponds to a mean duration of the detectable preclinical phase (DPCP) of 10-14 years, given that the cancers were detected on average at the midpoint of the DPCP., Conclusions: The findings suggest that a screening interval substantially longer than the 2 years generally used for mammography screening is unlikely to cause a substantial loss of sensitivity. A long screening interval is further justified in order to diminish the extent of overdiagnosis, until mortality effects can be evaluated.

High serum levels of insulin-like growth factor I (IGF-I) and low levels of IGF-binding protein-3 (IGFBP-3) have been shown to correlate with increased prostate cancer risk. To evaluate this, IGF-I, IGFBP-3, and prostate-specific antigen (PSA) were measured in serum from 665 consecutive men (179 with prostate cancer), aged 55-67 yr, with elevated serum prostate-specific antigen (PSA; > or = 4 microg/L) in a screening trial. Men in the highest quartile of IGF-I levels had an odds ratio (OR) for prostate cancer of 0.50 [95% confidence interval (CI) 0.26-0.97] when adjusting for serum IGFBP-3. IGFBP-3 itself was not significantly associated with prostate cancer risk (OR, 1.24; 95% CI, 0.68-2.24). Prostate volume was larger in men without than in those with prostate cancer (P < 0.001), and after adjustment for prostate volume, the negative association between serum IGF-I and prostate cancer risk was no longer significant (OR, 0.57; 95% CI, 0.28-1.16). In screen-positive men with elevated serum PSA, serum IGF-I is not a useful diagnostic test for prostate cancer, but it may be associated with benign prostatic hyperplasia and enlargement.

Prostate-specific antigen (PSA) rapidly forms a complex with alpha2-macroglobulin (A2M) in vitro; however, PSA complexed with A2M (PSA-A2M) is not detected by conventional immunoassays for PSA because it is encapsulated by the A2M. In this study, we show that denaturation of PSA-A2M at high pH renders PSA immunoreactive. Part of the complexed PSA is released in free form and part remains bound to denatured A2M. These forms can be measured by a conventional immunoassay for PSA. This finding enabled us to design a dissociation assay for the detection of PSA-A2M, which was based on the removal of immunoreactive PSA in serum by immunoadsorption, denaturation of PSA-A2M at high pH, and measurement of the released PSA immunoreactivity by a conventional PSA immunoassay. This PSA-A2M assay was calibrated with PSA-A2M formed in vitro. The detection limit of the assay was 0.14 microg/L. Inter- and intraassay coefficients variation were 4-9% and 8-14%, respectively. When purified PSA was incubated with A2M, the loss of PSA immunoreactivity was highly correlated with the PSA-A2M formed, as measured by the dissociation assay for PSA-A2M (r = 0.99; P <0.0001). The concentration of PSA-A2M in serum correlated with that of total PSA both in prostate cancer (PCa) and benign prostatic hyperplasia (BPH); however, the ratio of PSA-A2M in relation to total PSA was significantly higher in BPH than in PCa (P <0.0003). ROC curve analysis suggested that measurement of the ratio of PSA-A2M to total PSA in serum improves the diagnostic accuracy for PCa compared with assays for total PSA only.

In the present study an in vitro model was developed and characterized for evaluation of the role of apoptosis in adult human testes. The samples came from adult men undergoing orchidectomy for prostate or testicular cancer. Segments of seminiferous tubules were isolated and incubated under serum-free conditions in the absence or presence of testosterone. Apoptosis was assessed by low mol wt DNA fragmentation (185-bp multiples) by use of 3'-end-labeled DNA, in situ end labeling, and morphological detection under light and electron microscopy. During the 4-h incubation, a 15-fold increase was seen in apoptotic DNA fragmentation. The extent of low mol wt DNA showed a time-dependent increase and reached a 20-fold intensity in 24 h of incubation compared to the level at 0 h. Apoptosis was significantly suppressed by testosterone concentrations of 10(-7) and 10(-6) mol/L during the first 4 h of incubation. Apoptotic cells were identified mainly as spermatocytes and occasionally as spermatids. We conclude that apoptosis is induced in human seminiferous tubules under serum-free conditions in vitro. That this apoptosis is suppressed by testosterone indicates that testosterone in the human male is a critical germ cell survival factor. The model created in the present study provides a valuable tool for further investigation of hormonal and gene regulation of human germ cell death and survival.

The mechanism by which acute insulin administration alters VLDL apolipoprotein (apo) B subclass metabolism and thus plasma triglyceride concentration was evaluated in 7 normolipidemic healthy men on two occasions, during a saline infusion and during an 8.5-hour euglycemic hyperinsulinemic clamp (serum insulin, 490 +/- 30 pmol/L). During the insulin infusion, plasma triglycerides decreased by 22% (P < .05), and serum free fatty acid decreased by 85% (P < .05). The plasma concentration of VLDL1 apo B fell 32% during the insulin infusion, while that of VLDL2 apo B remained constant. A bolus injection of [3-(2)H]leucine was given on both occasions to trace apo B kinetics in the VLDL1 and VLDL2 subclasses (Svedberg flotation rate, 60-400 and 20-60, respectively), and the kinetic basis for the change in VLDL levels caused by insulin was examined using a non-steady-state multicompartmental model. The mean rate of VLDL1 apo B synthesis decreased significantly by 35% (P < .05) after 0.5 hour of the insulin infusion (523 +/- 87 mg/d) compared with the saline infusion (808 +/- 91 mg/d). This parameter was allowed to vary with time to explain the fall in VLDL1 concentration. After 8.5 hours of hyperinsulinemia, the rate of VLDL1 apo B synthesis was 51% lower (321 +/- 105 mg/d) than during the saline infusion (651 +/- 81 mg/d, P < .05). VLDL2 apo B production was similar during the saline (269 +/- 35 mg/d) and insulin (265 +/- 37 mg/d) infusions. No significant changes were observed in the fractional catabolic rates of either VLDL1 or VLDL2 apo B. We conclude that acute hyperinsulinemia lowers plasma triglyceride and VLDL levels principally by suppressing VLDL1 apo B production but has no effect on VLDL2 apo B production. These findings indicate that the rates of VLDL1 and VLDL2 apo B production in the liver are independently regulated.

We have studied the forms of prostate-specific antigen (PSA) in serum of patients with prostatic cancer and benign prostatic hyperplasia. Fractionation of serum by gel filtration and assay of the fractions for PSA showed that a considerable part of the PSA immunoreactivity in serum consisted of complexes that were larger than PSA. The complexes were assayed by time-resolved immunofluorometric assays based on an antibody against PSA on the solid phase and europium-labeled antibodies against various protease inhibitors as indicator antibodies. In addition to its monomeric form, PSA was found to occur in complex with alpha 1-antichymotrypsin. The proportion of the alpha 1-antichymotrypsin complex was a major form of PSA and it increased with increasing PSA concentrations, being over 85% at PSA levels exceeding 1000 micrograms/liter. A complex with alpha 1-protease inhibitor was also observed in serum of patients with prostatic cancer and very high levels of PSA. Complexes with alpha 2-macroglobulin and inter-alpha-trypsin inhibitor were detected, but their concentrations were low and similar in sera of cancer patients, normal men, and normal women, suggesting that they were not prostate derived. Commercial immunoradiometric assays for PSA were found to measure free PSA and its complexes with alpha 1-antichymotrypsin but not the complexes with alpha 2-macroglobulin and inter-alpha-trypsin inhibitor. The proportion of the PSA-alpha 1-antichymotrypsin complex was higher in patients with prostatic cancer than in those with benign hyperplasia. Therefore, assay of the complex had a higher sensitivity for cancer than assay of total PSA immunoreactivity.

Luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone (T) responses to 6-month treatments with a gonadotropin-releasing hormone (GnRH) agonist (buserelin) and subsequent orchiectomy were studied in patients with advanced prostate cancer. For treatments, either an intranasal (600 micrograms, 3/day, n = 8) or subcutaneous depot preparation (6.6 mg every other month, n = 5) were used. A third group of patients received intranasal buserelin (400 micrograms, 3/day, n = 12) for 35 months. LH and FSH were measured using radioimmunoassay (RIA) and a sensitive (0.04 IU/L) immunofluorometric assay (IFMA). In addition, selected samples were analyzed for bioactive (bio) LH. The RIA-LH levels decreased 70% with intranasal treatment. In contrast, when monitored by IFMA, the reduction was greater than 90%: 0.2 to 0.3 IU/L with intranasal and 0.044 to 0.052 IU/L with depot treatment (P less than 0.01). Gonadotropin suppression was stable up to 35 months. Bio-LH and IFMA-LH levels decreased in parallel during treatment, with no apparent changes in the bio/immuno ratio. FSH levels were suppressed temporarily during the treatments. After castration and cessation of buserelin treatment, serum LH and FSH increased rapidly in the intranasal treatment group but only marginally during 3 months in the depot group. Serum T reached the castrate range when IFMA-LH decreased below 0.5 IU/L. A further decrease in LH (less than 0.1 IU/L) still suppressed the intratesticular T concentration measured after orchiectomy. In conclusion, IFMA offers an improved method to monitor the antigonadotropic effect of GnRH agonist treatment. The results emphasize the necessity of profound LH suppression to achieve maximal inhibition of testicular androgen production.

Endogenous testosterone (T), LH and FSH receptors, and in vitro production of cyclic adenosine-3':5'-monophosphate (cAMP), T and some of its steroid precursors were measured in testicular tissue obtained at orchiectomy from seven prostatic cancer patients treated for 6 months with a potent gonadotropin-releasing hormone (GnRH) agonist analog (buserelin, Hoechst, 600 micrograms 3 times a day intranasally). In addition, histologic and morphometric studies were carried out on the testicular tissue. Testicular tissue from age-matched prostatic cancer patients (n = 14), whose first therapy was orchiectomy, served as controls. The peptide treatment decreased intratesticular T by 95% (P less than 0.01) and FSH receptors by 57% (P less than 0.01), but had no effect on LH receptors. The in vitro production of T decreased by 94% (P less than 0.01), but that of cAMP was unaffected. Besides T, the in vitro production of testicular 17-hydroxyprogesterone (17-OHP-4), androstenedione and 5 alpha-dihydrotestosterone (5 alpha-DHT) dropped by 71 to 90% (P less than 0.01 to 0.05) during buserelin treatment, but those of pregnenolone, progesterone and dehydroepiandrosterone (DHEA) were not affected. Histologic studies revealed considerable variation in the seminiferous epithelium of the control group, but spermatogenesis was highly suppressed in nearly all of the buserelin-treated group. The number of Sertoli cells was unaffected, but tubular diameters were reduced (P less than 0.05) by buserelin treatment. Leydig cells appeared dedifferentiated in this group, although their number per testis was not altered. These data indicate that gonadotropin suppression by GnRH agonist most likely affects testicular steroidogenesis by inhibiting 3 beta-hydroxysteroid dehydrogenase and a step(s) prior to pregnenolone formation. The treatment does not impair testicular LH binding or cAMP production, but clearly suppresses FSH receptors. Spermatogenesis in general is suppressed but with considerable variation.

Eight patients with advanced prostatic carcinoma (ages 59 to 78 years) were treated with a potent gonadotropin-releasing hormone (GnRH) agonist analog (buserelin, Hoechst; 600 micrograms intranasally, 3 times daily) and orchiectomized after 6 months of treatment. Endocrine responses were followed by serum hormone measurements during agonist treatment and for 3 months after orchiectomy. Six other patients (65 to 86 years) with advanced prostatic cancer had been orchiectomized as the first therapeutic measure and their blood samples were used as controls. In the GnRH agonist-treated patients, serum immunoreactive luteinizing hormone (LH) and follicle stimulating hormone (FSH) decreased after initial stimulation by 70 to 80%, within 1 to 3 weeks (P less than 0.01). FSH partly recovered (P less than 0.05) after the first month of treatment. Serum prolactin (PRL) displayed a slight tendency to decline during buserelin treatment (P less than 0.05). Serum total and free testosterone (T) of the buserelin-treated patients decreased to the castrate range within 3 to 4 weeks after an initial 5-day increase (P less than 0.01). Serum progesterone and 17-hydroxyprogesterone (17-OHP-4) decreased to the castrate range (by 50 to 70%) in 1 week. Only minor changes were observed in sex hormone binding globulin (SHBG). Significant, acute elevations of LH, FSH, T, and 17-OHP-4 were observed only on day 1 after an injection of buserelin (500 microgram i.m.) and not when assessed between day 7 and month 6 of treatment. After 6 months of buserelin treatment, orchiectomy did not affect the serum steroids measured. After orchiectomy, immediate increases in serum LH, and somewhat later in FSH, were seen in the control patients.(ABSTRACT TRUNCATED AT 250 WORDS)