Proliferation und Apoptose vor und nach präoperativer simultaner Radiochemotherapie von Rektumkarzinomen

Purpose

To investigate the relationship between apoptotic cell death, proliferative activity, and the status of the tumor suppressor gene p53 in rectal cancer before and after radiochemotherapy.

Materials and Methods

Thirty-two patients dispositioned to receive preoperative radiochemotherapy for locally advanced rectal carcinoma prior to radical surgical tumor resection were analysed. In all cases, pretherapy biopsies and the final resected specimens after radiochemotherapy were available for analyses. Apoptotic cells were identified and quantified using in situ end labeling (ISEL) technique. The proliferative activity was determined by immunohistochemical assessment of the Ki67 (MIB-1) antigen. p53 expression was analysed immunohistochemically as well. A clinical-to-pathologic downstaging after radiochemotherapy was achieved in 25/32 patients (78%). In one case, no residual tumor was detected after radiochemotherapy.

Results

After radiochemotherapy, the apoptotic index increased significantly in almost every case examined. In contrast, the proliferative activity was significantly decreased when comparing biopsies and resected specimens. Tumors that were immunohistochemically negative for p53 generally exhibited a higher apoptotic index than p53 positive tumors. However, we did not find any correlation between the (pre- and post-therapeutic) rate of apoptosis and the degree of clinical-to-pathologic downstaging.

Conclusion

Our results indicate, that radiochemotherapy induces an increase in apoptotic cell death. The observation of higher rates of apoptosis in p53 negative tumors suggests that p53 might be a regulator of apoptosis in rectal cancer.     

Sonoelastography of the prostate: comparison with systematic biopsy findings in 492 patients

OBJECTIVE: The aim of this study was to assess the value of sonoelastography (SE) for prostate cancer detection in comparison with systematic biopsy findings. MATERIAL AND METHODS: Four hundred and ninety two PSA screening volunteers (mean age: 61.9+/-8.6) with an total PSA >1.25 ng/mL and a free to total PSA ration of <18% underwent SE of the prostate before 10 core systematic prostate biopsy. Tissue elasticity of the peripheral zone was investigated only. Tissue elasticity was displayed from red (soft) to green (intermediate) and to blue (hard). Only hard lesions (blue) were considered to be suspicious for prostate cancer. The peripheral zone of the prostate was divided in 3 regions on each side: base, mid-gland, apex. A different investigator performed systematic biopsy, and the biopsy findings were compared with the SE findings. RESULTS: In 125 of 492 patients (25.4%) systematic biopsy demonstrated prostate cancer. Cancer was detected in 321 of 2952 (11%) outer gland areas (74 in the base, 106 in the mid-gland, 141 in the apex). The Gleason score ranged from 3 to 10 (mean: 6.5). In SE 533 of 2952 (18.1%) suspicious areas were detected and 258 of these areas (48.4%) showed cancer. Most of the false-positive findings (275/533 areas; 51.6%) were associated with chronic inflammation and atrophy especially at the basal prostate areas. The sensitivity by entire organ was calculated with 86% and the specificity 72%. The analysis by outer gland areas showed the highest sensitivity in the apex (79%). The specificity by outer gland areas ranged between 85% and 93%. The correlation between SE findings and biopsy results was high (p<0.001). CONCLUSION: Sonoelastography findings showed a good correlation with the systematic biopsy results. The best sensitivity and specificity was found in the apex region. Sonoelastography seems to offer a new approach for differentiation of tissue stiffness of the prostate and may therefore improve prostate cancer detection.     

Dutasteride prior to contrast-enhanced colour Doppler ultrasound prostate biopsy increases prostate cancer detection

OBJECTIVES: This study assessed the effect of premedication with dutasteride, a dual 5alpha-reductase inhibitor, on prostatic blood flow prior to prostate biopsy and its impact on prostate cancer detection. METHODS: Thirty-six patients, aged 52-74 yr, with elevated prostate-specific antigen (PSA) levels (>or=1.25 ng/ml and free-to-total ratio of <18%) were treated with dutasteride 14 d prior to prostate biopsy. Contrast-enhanced colour Doppler (CECD) ultrasound was performed before and 7 and 14 d after dutasteride treatment. Contrast-enhanced targeted biopsies (相似文献   

CD4 coating, but not CD4 depletion, is a predictor of efficacy with primatized monoclonal anti-CD4 treatment of active rheumatoid arthritis

OBJECTIVE: Double blind studies were conducted with the anti-CD4 monoclonal antibody (Mab) keliximab in patients with active, stable rheumatoid arthritis (RA), to confirm preliminary evidence of efficacy and safety from open. uncontrolled studies. METHODS: We enrolled 136 and 186 patients into 2 consecutive, randomized, double blind trials, with similar populations [apart from inclusion of disease modifying antirheumatic drug (DMARD)-na?ve patients in Study 2]. Patients received 4 weeks intravenous placebo or keliximab [40, 80, 120, or 140 mg twice weekly (bw), or 240 mg once weekly (ow)].The primary endpoint was the American College of Rheumatology (ACR) 20 response criteria, one week after the end of treatment. RESULTS: ACR 20 response rates in Study I were 19%, 42%, 51%*, and 69%* (*p < 0.05 compared to placebo), with placebo, 40, 80, or 140 mg keliximab bw, respectively. The response rates in Study 2 were 30%, 39%, 46% and 47% with placebo, 80 or 120 mg bw, or 240 mg keliximab ow, respectively. In the 2 studies, there was a dose dependent increase in peripheral blood CD4+ T cell coating with keliximab, but a different pattern of CD4 depletion was seen. While only 12% of keliximab treated patients in Study I had CD4 counts below 250 cells/mm3 at the end of the treatment period, 47% fell below this level in Study 2. Clinical response was not correlated with CD4 depletion, but was correlated with CD4+ T cell coating with keliximab. CONCLUSION: Coating of peripheral blood CD4+ T cells with keliximab, but not CD4 depletion, is a determinant of clinical response.     

The effect of exercise training in symptomatic patients with grown-up congenital heart disease: a review

Introduction: The number of grown-up congenital heart disease (GUCH) patients is steadily increasing. Unfortunately, the majority of these patients suffer from late sequelae, with heart failure being the most common cause of death. Exercise training is beneficial and safe in patients with acquired heart failure, as well as in asymptomatic GUCH patients. However, its effect remains unknown in symptomatic GUCH patients. This could cause reticence on positive sports advice, with possible counterproductive effects.

Areas covered: A review of current literature was performed to evaluate the effect of exercise training in symptomatic (NYHA≥2) GUCH patients. The search yielded a mere three studies including symptomatic patients, and another six studies including also patients in NYHA 1 without making clear distinction between the NYHA subgroups.

Expert commentary: Suboptimal trial designs, low patient numbers, and homogeneity of investigated cardiac anomalies make this review insufficient to draw definite conclusions. However, all studies describe overall positive effects of exercise training in symptomatic GUCH patients in terms of exercise capacity and quality of life. There were no safety concerns. Larger-scaled, randomized controlled trials are needed to obtain certainty.     

Safety of long-term interruption of successful antiretroviral therapy: the ATHENA cohort study

We studied the dynamics of CD4 cell counts after the interruption of virologically successful highly active antiretroviral therapy (HAART) in 139 patients. Changes in CD4 cell counts during HAART interruption followed a biphasic pattern: an initial rapid decline during the first month followed by a slow decrease. During 48 weeks of follow-up mean CD4 cell counts remained just above the mean pre-HAART level. This limits the feasibility of structured treatment interruptions for patients with low nadir CD4 cell counts.     

Age-related changes in processing positive and negative feedback: Is there a positivity effect for older adults?

Older people sometimes show a bias toward the processing of positive information. In this study, we used an event-related potential approach to examine whether such a positivity bias is also present during feedback processing in older adults. Our results suggest that a fast initial monitoring process, as reflected in the feedback-related negativity (FRN), is sensitive to the expectancy of events irrespective of their valence for older (aged 70–77 years) as well as younger (aged 20–27 years) adults. In contrast, in a later evaluation process, associated with memory updating and indexed by the P300, both age groups preferably processed unexpected positive feedback. However, younger adults additionally differentiated between unexpected negative and expected feedback while older adults did not, probably due to a lower working memory capacity.     

Transthyretin Is Dysregulated in Preeclampsia,and Its Native Form Prevents the Onset of Disease in a Preclinical Mouse Model

Preeclampsia is a major pregnancy complication with potential short- and long-term consequences for both mother and fetus. Understanding its pathogenesis and causative biomarkers is likely to yield insights for prediction and treatment. Herein, we provide evidence that transthyretin, a transporter of thyroxine and retinol, is aggregated in preeclampsia and is present at reduced levels in sera of preeclamptic women, as detected by proteomic screen. We demonstrate that transthyretin aggregates form deposits in preeclampsia placental tissue and cause apoptosis. By using in vitro approaches and a humanized mouse model, we provide evidence for a causal link between dysregulated transthyretin and preeclampsia. Native transthyretin inhibits all preeclampsia-like features in the humanized mouse model, including new-onset proteinuria, increased blood pressure, glomerular endotheliosis, and production of anti-angiogenic factors. Our findings suggest that a focus on transthyretin structure and function is a novel strategy to understand and combat preeclampsia.Preeclampsia occurs in 5% to 8% of pregnancies worldwide and is a major cause of fetal and maternal morbidity and mortality.^1–3 It is a heterogeneous disease with varied presentations from mild self-limited hypertension and proteinuria to severe forms with significant end-organ dysfunction and HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets).³ Although the cause of preeclampsia and its appropriate treatment remain elusive, this syndrome has been proposed to reflect at least two stages of complications during pregnancy. These begin with preclinical manifestations at the maternal-fetal interface, followed by systemic clinical symptoms.^1,2 Hypertension, proteinuria, and edema, with a variable degree of fetal growth restriction, are the cardinal features of preeclampsia.³ Because the placenta is the nutritional and immunological gateway to normal fetal development and pregnancy outcome, placenta-related events are believed to be central to the pathogenesis of this disease. Evidence exists for the release of disease-initiating molecules into maternal circulation that triggers the clinical symptoms.^1,4 Placental and systemic anomalies reflected by circulating placental debris, inflammation, impaired remodeling of spiral arteries, placental hypoxia/ischemia, excess production of anti-angiogenic factors [soluble fms-like tyrosine kinase-1 (sFlt-1)], and soluble endoglin (sEng), and angiotensin receptor autoantibodies have all emerged as contributors to the pathophysiological characteristics of preeclampsia.^2,4–14Preeclampsia has remained enigmatic because of lack of well-defined etiology and animal models. Although normal mice do not develop preeclampsia spontaneously, mouse models have been judged to be particularly useful to uterine diseases and pregnancy complications because many similarities in female reproduction and placentation have been identified between the two species.¹⁵ Moreover, their tractable genetics provide an effective way to probe mechanisms more deeply than many other species.^15–17 We recently showed that sera from preeclamptic women could function as a source of novel causative factors that induced hypertension, proteinuria, and kidney pathological characteristics, as well as intrauterine growth restriction (IUGR), in IL-10^−/− mice in a pregnancy-specific manner.¹⁸ IL-10 functions as a potent vascular and anti-inflammatory cytokine and has been shown to be present at significantly reduced levels in preeclampsia placental tissue.^19,20 Preeclampsia serum (PES) was found to disrupt endovascular cross talk between trophoblasts and endothelial cells and to induce placental hypoxia and excess production of sFlt-1 and sEng,¹⁸ soluble factors known to precipitate maternal symptoms.^21,22 These results from our serum-based humanized mouse model suggest that the pathophysiological characteristics of preeclampsia are more complex than previously thought and are likely to involve interactions and dysregulation of multiple factors. By using serum proteomic screening by surface-enhanced laser-desorption ionization-time-of-flight (SELDI-TOF), our results suggest that PES contains a reduced abundance of transthyretin, a plasma transport protein for the thyroid hormone, thyroxine, and retinol-binding protein.²³ More important, transthyretin has been widely studied for its role in amyloid diseases associated with protein misfolding and aggregation, resulting in deposits of toxic, fibrillar aggregates in specific organs.^24–26 Dysregulated or reduced transthyretin has also been implicated in Alzheimer disease, and overexpression of a wild-type human transthyretin transgene has been shown to ameliorate the disease in the transgenic murine model of human Alzheimer disease.^27,28 Transthyretin in its native form assumes a homotetrameric quaternary configuration (approximately 14 kDa per monomer). Post-translational modifications of the monomer result in detection of several isoforms.²⁹ Circulating transthyretin is also a validated marker of malnutrition and has a putative role in oocyte maturation and inflammation.^30–32 Although the presence of transthyretin during implantation in mice and in the placenta and trophoblasts in humans has been reported,^33,34 its functional role in normal pregnancy or adverse pregnancy outcomes has not been recognized. We hypothesize that transthyretin in preeclampsia is structurally and functionally dysregulated and contributes to the onset of this serious pregnancy complication. Herein, we present complementary in vitro and in vivo approaches, which show that endogenously altered transthyretin is a preeclampsia-causing agent and that native transthyretin has the ability to block the onset of preeclampsia-like features.