An association of Bcl-2 phosphorylation and Bax localization with their functions after hyperthermia and paclitaxel treatment

Apoptosis is induced by many kinds of therapy-related inducers, such as hyperthermia and chemotherapeutic agents. However, differences in apoptotic pathways between these inducers remain unclear, although knowing the differences is important to map out a therapeutic strategy. Therefore, we focused on the localization and phosphorylation of Bcl-2 and Bax, key mediators of the apoptotic pathway, after hyperthermia and paclitaxel treatment of PC-10 squamous cell carcinoma cells that excessively expressed Bcl-2 and Bax in the cytoplasm. Paclitaxel treatment markedly induced qualitative changes in Bcl-2, whereas hyperthermia did only quantitative changes in Bax. The levels of Bax increased gradually with the duration of hyperthermia, whereas Bcl-2 levels slightly decreased. On the other hand, paclitaxel treatment induced dose- and time-dependent phosphorylation of Bcl-2. Interestingly, phosphorylated Bcl-2 was observed in the specific subcellular sites, mitochondria- and lysosome-rich fractions. Both treatments disturbed the heterodimerization of Bax with Bcl-2. Hyperthermia, but not paclitaxel treatment, induced a gradual Bax translocation from the cytoplasm to the nucleus. Although both treatments induced a prominent cell cycle disturbance in the G2M phase, paclitaxel treatment induced typical apoptosis, and hyperthermia hardly induced apoptosis. Our results suggest that the subcellular redistribution of Bax and the phosphorylation of Bcl-2 depend on the type of apoptosis inducers, such as hyperthermia and paclitaxel, and Bcl-2 has a central role in the decision of apoptotic outcome. Our data may afford new insights in apoptosis from the aspect of an association of Bcl-2 phosphorylation with intracellular Bax localization.     

Transurethral resection vs microwave thermotherapy of the prostate: a cost-consequences analysis

OBJECTIVE: To compare the costs and outcome of high-energy transurethral microwave thermotherapy of the prostate (HE-TUMT) with transurethral resection of the prostate (TURP), as the former is considered to be the best minimally invasive method for managing lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH). PATIENTS AND METHODS: Between January 1996 and March 1997, 144 patients were randomized to treatment with HE-TUMT (78) using the Prostatron device and Prostasoft 2.5 software (EDAP Technomed, Lyon, France), or TURP (66). At baseline and during the annual follow-up, patients were evaluated by the International Prostate Symptom Score and uroflowmetry (maximum flow rate and postvoid residual volume). Kaplan-Meier survival analyses were used to calculate the cumulative risk of re-treatment. A cost-consequences analysis was performed based on the prospective measurement of healthcare use, with costs expressed as Netherland guilders (NLG). RESULTS: During a 3-year follow-up period, the mean (95% confidence interval) risk of re-treatment was 22.9 (12.5-33.2)% and 13.2 (4.5-21.9)% for HE-TUMT and TURP, respectively (P = 0.215). The mean direct cost of treatment was 3450 (3444-3456) and 6560 (5992-7128) NLG for HE-TUMT and TURP, respectively. The mean total (including re-treatments), discounted (4%) 3-year cost for the HE-TUMT and TURP group was 5300 (4692-5908) and 7800 (7118-8482) NLG, respectively. CONCLUSIONS: In this prospective randomized trial, HE-TUMT and TURP had a comparable 3-year risk of re-treatment. Healthcare expenditure on HE-TUMT, mainly because it is an outpatient treatment, was significantly lower than for TURP.     

Brain capillaries and cholinergic neurons persist in organotypic brain slices in the absence of blood flow

Angiogenesis plays an important role during development of the brain and under pathological conditions. The aim of the present study was to observe interaction of brain capillaries and cholinergic neurons in organotypic brain slices. Immunohistochemistry was used to visualize brain capillary-like structures (RECA-1 antigen) and cholinergic neurons (choline acetyltransferase). Under normal culture conditions, a very low number of brain capillaries was found in 2- and 4-week-old cortex brain slices. Treatment of slices with acidic medium (pH 6) or hyperthermia (42 degrees C) markedly enhanced the number of brain capillaries. Incubation with 10 ng/mL vascular endothelial growth factor only enhanced angiogenesis in more developed slices. Cholinergic neurons survived in slices of the basal nucleus of Meynert; however, hyperthermia but not acidosis markedly decreased their number. In coslices of the basal nucleus of Meynert and cortex (pretreated with acidic medium), a high number of RECA-1-positive capillaries and cholinergic neurons persisted and displayed strong nerve fibre growth of cholinergic fibres into the cortex. In conclusion, we have demonstrated that RECA-1-positive capillaries and cholinergic neurons can be studied in slice cultures in the absence of blood perfusion, and that this model could provide a system to study mechanisms involved in vascular dementia.     

Clinical Management of Neuroleptic Malignant Syndrome

Neuroleptic malignant syndrome (NMS) continues to be an unpredictable and rare, but potentially fatal complication of antipsychotic medications. Presumptively linked to dopamine blockade, it nonetheless occurs in patients receiving newer atypical antipsychotics. The features of NMS, its pathophysiology, differential diagnosis, clinical course, risk factors, and morbidity and motality are reviewed. Nonpharmacologic management centers on aggressive supportive care including vigilant nursing, physical therapy, cooling, rehydration, anticoagulation. Pharmacologic interventions include immediate discontinuation of antipsychotics, judicious use of anticholinergics, and adjunctive benzodiazepines. The utility of specific agents in actively treating NMS is reviewed. Bromocriptine and other dopaminergic drugs and dantrolene sodium have alternatively been considered without merit or efficacious. Guidelines for using these agents are presented. Electroconvulsive therapy, also somewhat controversial, is identified as a second line of treatment. Finally, management of the post-NMS patient is also reviewed.     

Effects of lubeluzole on the methamphetamine-induced increase in extracellular glutamate and the long-term depletion of striatal dopamine

The administration of a neurotoxic regimen of methamphetamine (MA) produces an acute elevation in the extracellular concentrations of dopamine and glutamate in the striatum and a long-term depletion of striatal dopamine content in rats. The intent of the present study was to determine whether attenuation of the MA-induced increase in extracellular glutamate would prevent the depletion of striatal dopamine. Male rats were treated with MA (10 mg/kg, i.p.) or vehicle every 2 h for four injections and concomitantly perfused intrastriatally with either artificial cerebrospinal fluid or lubeluzole (300 microM), a novel neuroprotectant that has been shown to prevent the increase in extracellular glutamate after the induction of neocortical infarct in rats. Lubeluzole significantly attenuated the MA-induced increase in extracellular glutamate in the striatum without affecting the MA-induced increase in extracellular dopamine or the MA-induced hyperthermic response. Nevertheless, lubeluzole did not prevent the long-term depletion of striatal dopamine produced by a neurotoxic regimen of MA. These results suggest that the MA-induced depletion of striatal dopamine may not be dependent on the increased extracellular concentration of striatal glutamate.     

Hypoxia-regulated p53 and its effect on radiosensitivity in cancer cells

Purpose: To determine the response of tumor suppressor p53 to hypoxia in different tumor cell lines and the involvement of p53 activity regulation in the effect of hypoxia on tumor cell sensitivity to radiation and hyperthermia.

Materials and methods: Three tumor cell lines with functional p53 were treated with chronic or cyclic hypoxia followed by radiation or hyperthermia to investigate p53 activity and cell survival. Flow cytometry was used to investigate the effect of hypoxia-induced cell cycle arrest on radiosensitivity in KHT-C (mouse fibrosarcoma) cells. Transient transfection was performed to determine the role of altered p53 activity in KHT-C and SCC VII (mouse squamous-cell carcinoma) radiosensitivity.

Results: Aerobic radiosensitivity was decreased in KHT-C and SCC VII cells after in vitro chronic or cyclic hypoxia pretreatment, but in HT1080 cells, it was slightly increased after chronic hypoxia, and was unchanged after acute hypoxia pretreatment. Decreased radiosensitivity in hypoxia-pretreated KHT-C and SCC VII cells was unlikely due to hypoxia-induced cell cycle arrest, but rather seemed to be associated with increased expression of Mdm2 (mouse double minute-2) and decreased p53. Furthermore, hypoxia pretreatment inhibited the activation of p53 by radiation. Similar results were observed in hyperthermia treated KHT-C cells. Finally, decreased radiosensitivity was observed in both KHT-C and SCC VII cells transiently transfected with Mdm2 or anti-sense p53 cDNA.

Conclusion: We demonstrated that hypoxia may decrease tumor cell radiosensitivity through the suppression of p53 activity in some tumor cell lines. These results suggested the response of p53 to hypoxia can be cell type specific and contribute to radiosensitivity of hypoxic cells.     

胃肠道癌术后腹腔持续热灌注化疗

[目的]探讨腹腔持续热灌注化疗治疗胃肠道癌的近期疗效。[方法]162例住院病人随机分为治疗组及对照组,治疗组病人腹腔持续热灌庄化疗,对照组病人作常规静脉化疗。[结果]治疗组1年生存率为38.9％,对照组为23.6％（P<0.05）。毒副作用以白细胞下降、胃肠道反应及肝肾功能损害为主,治疗组明显低于对照组。[结论]胃肠道癌术后行腹腔持续热灌注化疗副作用小,1年生存率高。     

Rapid cooling in classic heatstroke: Effect on mortality rates

The case records of 39 patients with classic (non-exertional) heatstroke presenting to an urban emergency department were reviewed. Eight of 39 patients died. Rapid cooling, defined as a rectal temperature of less than or equal to 38.9 degrees C (102 degrees F) within an hour of presentation, was achieved in 27 of 39 patients. Twelve patients had a temperature greater than or equal to 38.9 degrees C (102 degrees F) after one hour of treatment in the emergency department. The rate of mortality in the rapid cooling group was four of 27 (15%), while in the delayed cooling group, the mortality rate was four of 12 (33%) (P = 0.18). Factors such as advanced age, hypotension, altered coagulation status, and the necessity for endotracheal intubation on presentation dictated a poor outcome despite successful cooling measures.     

中医辨证调护配合微波热疗治疗慢性非细菌性前列腺炎35例

目的:观察中医辨证调护配合微波热疗治疗慢性非细菌性前列腺炎的疗效进行总结分析。方法:将65例慢性非细菌性前列腺炎患者随机分为治疗组35例和对照组30例。对治疗组使用微波热疗配合中医辨证调护进行治疗,对照组给予反复前列腺按摩法治疗。观察两组患者的临床疗效、提前出院率及复发率。结果:治疗组有效率为97.14%,对照组有效率为66.67%,两组患者临床疗效比较,差异具有统计学意义(P0.05)。治疗组提前出院率高于对照组,复发率低于对照组,差异均有统计学意义(P0.05)。结论:中医辨证调护配合微波热疗治疗慢性非细菌性前列腺炎临床疗效显著,复发率低。     

Quadrimodal treatment of high-risk T1 and T2 bladder cancer: Transurethral tumor resection followed by concurrent radiochemotherapy and regional deep hyperthermia

Background and purpose

To assess the safety and effectiveness of treating high-risk T1 and T2 bladder cancer with transurethral resection (TUR-BT) followed by radiochemotherapy (RCT) combined with regional deep hyperthermia (RHT).

Material and methods

Between 2003 and 2007, 45 patients were enrolled. After TUR-BT patients received radiotherapy (RT) of the bladder and regional lymph nodes with 50.4 Gy, and a boost to the bladder of 5.4-9 Gy. RCT was applied to 43/45 patients. RHT was administered once weekly. Response was re-evaluated 6 weeks after RT by restaging-TUR. Toxicity was graded with the CTCAE, version 3.0. QoL was evaluated by a dedicated questionnaire.

Results

The median follow-up was 34 months (range 12-60). The median number of hyperthermia treatments was 5 (range 1-7). Acute toxicity grades 3 and 4 occurred in 20% (9/45) and 9% (4/45), respectively. Late toxicity grades 3/4 were seen in 24% (11/45). Complete response rate was 96% (43/45). Local recurrence-free survival was 85%, overall survival was 80%, disease-specific survival was 88%, metastasis-free survival was 89%, and the bladder-preserving rate was 96% (43/45) at 3 years. Eighty percent (24/30) were at least mostly satisfied with their bladder function.

Conclusions

The quadrimodal treatment was feasible and well tolerated. Local control and bladder-preserving rates were encouraging.