A chemical biology screen identifies glucocorticoids that regulate c-maf expression by increasing its proteasomal degradation through up-regulation of ubiquitin

The oncogene c-maf is frequently overexpressed in multiple myeloma cell lines and patient samples and contributes to increased cellular proliferation in part by inducing cyclin D2 expression. To identify regulators of c-maf, we developed a chemical screen in NIH3T3 cells stably overexpressing c-maf and the cyclin D2 promoter driving luciferase. From a screen of 2400 off-patent drugs and chemicals, we identified glucocorticoids as c-maf-dependent inhibitors of cyclin D2 transactivation. In multiple myeloma cell lines, glucocorticoids reduced levels of c-maf protein without influencing corresponding mRNA levels. Subsequent studies demonstrated that glucocorticoids increased ubiquitination-dependent degradation of c-maf and up-regulated ubiquitin C mRNA. Moreover, ectopic expression of ubiquitin C recapitulated the effects of glucocorticoids, demonstrating regulation of c-maf protein through the abundance of the ubiquitin substrate. Thus, using a chemical biology approach, we identified a novel mechanism of action of glucocorticoids and a novel mechanism by which levels of c-maf protein are regulated by the abundance of the ubiquitin substrate.     

Restoration of cardiomyocyte functional properties by angiotensin II receptor blockade in diabetic rats

Recent evidence suggests that blockade of the renin-angiotensin system ameliorates diabetes-induced cardiac dysfunction, but the mechanisms involved in this process remain elusive. We investigated the effect of treatment with an angiotensin II receptor blocker, losartan, on the metabolic and electrophysiological properties of cardiomyocytes isolated from streptozotocin-induced diabetic (STZ) rats. Glucose uptake and electrophysiological properties were measured in ventricular cardiomyocytes from normoglycemic and STZ-induced diabetic rats given vehicle or 20 mg x kg(-1) x day(-1) losartan for 8 weeks. Insulin and beta-adrenergic stimulation failed to increase the glucose uptake rate in STZ cardiomyocytes, whereas the alpha-adrenergic effect persisted. Concurrently, a typical prolongation of action potential duration (APD) and a decrease of transient outward current (I(to)) were recorded in patch-clamped STZ myocytes. Treatment with losartan did not affect body weight or glycemia of diabetic or control animals. However, in losartan-treated STZ-induced diabetic rats, beta-adrenergic-mediated enhancement of glucose uptake was completely recovered. APD and I(to) were similar to those measured in losartan-treated control rats. A significant (P < 0.0001) correlation between metabolic and electrophysiological parameters was found in control, diabetic, and losartan-treated diabetic rats. Thus, angiotensin receptor blockade protects the heart from the development of cellular alterations typically associated with diabetes. These data suggest that angiotensin receptor blockers may represent a new therapeutic strategy for diabetic cardiomyopathy.     

Which patients with prostate cancer are actually candidates for hormone therapy?

In this article, we will try to address the following aspects: which factors are responsible of the introduction of new candidates for hormone therapy in prostate cancer, who are actually candidates for hormone therapy, classifying them on the basis of the stage of the disease, and which treatment modalities can be proposed for each candidate. Since the introduction of hormone therapy for the treatment of prostate cancer, there has been a debate about the optimal timing of hormone therapy. A modification in the timing of hormone therapy produced new candidates for hormone manipulation. In particular, the use of hormone treatment for younger patients, longer periods and early prostate cancer, absolutely requires a whole re-evaluation of which therapy is indicated and it may produce new problems such as higher risk of over-treatment, need of a better evaluation of quality of life in younger patients and the research for better tolerated therapies. Therapies that resist for longer periods without the production of a hormone-refractory disease are also required.     

Sentinel node mapping in high risk endometrial cancer after laparoscopic supracervical hysterectomy with morcellation

INTRODUCTIONOccult endometrial cancer after supracervical hysterectomy is very uncommon. Even if optimal management of those rare cases is still unproven, to guide the need for further therapies, restaging should be recommended in this situation.PRESENTATION OF CASEWe report of a 60-year old woman with occult high risk endometrial cancer after supracervical hysterectomy with morcellation. We describe the feasibility of laparoscopic intraoperative sentinel node identification with cervical stump removing to restage the suspicious early stage high risk endometrial cancer.DISCUSSIONIn high risk endometrial cancer surgical restaging is important, considering that 10–35% of cases can present pelvic nodal metastasis. To reduce the treatment related morbidity maintaining the benefit of surgical staging, with a negative preoperative PET/CT, we performed a laparoscopic SN mapping with cervical stump removing.CONCLUSIONThis report highlight the fact that SN mapping with cervical injection is a feasible and safe technique also without the uterine corpus after supracervical hysterectomy with morcellation.     

Adjuvant PEFG (Cisplatin, Epirubicin, 5-Fluorouracil, Gemcitabine) or Gemcitabine Followed by Chemoradiation in Pancreatic Cancer: A Randomized Phase II Trial

Background

Information from randomized trials on the role of combination chemotherapy in the adjuvant treatment of pancreatic adenocarcinoma is limited. This randomized phase II trial aimed to identify the most promising regimen warranting phase III evaluation.

Methods

Therapy-naive patients, age 18?C75?years, Karnofsky Performance Status (KPS) >60, gross total resection of stage IB?CIII pancreatic adenocarcinoma, stratified for center and surgical margins, were randomly assigned to receive either gemcitabine 1?g/m² weekly on days 1, 8, and 15 (arm A) or the PEFG regimen (cisplatin and epirubicin 40?mg/m², day 1; gemcitabine 600?mg/m², days 1, 8; 5-fluorouracil 200?mg/m² daily, days 1?C28) (arm B). Chemotherapy was administered every 4?weeks for 3?months and followed by irradiation concurrent to continuous infusion of 5-fluorouracil 250?mg/m² daily. Primary endpoint was the probability of being disease-free at 1?year from surgery. Assuming P0?=?35% and P1?=?55%, ???=?.05 and ???=?.10, the study was to enroll 51 patients per arm.

Results

A total of 102 patients were randomized; 100 were eligible (arm A: 51; arm B: 49). Baseline characteristic (A/B) were: Median age was 61/60?years; 75% had KPS >80 75/76%; 36% grade 3 tumor 29/43%, 79% stage IIB/III 75/84%, 31% R1 resection 35/29%. Survival figures (A/B) were: Median disease-free survival was 11.7 and 15.2?months; 1-year disease-free survival 49.0% (95% confidence interval [95% CI] 35?C63%) and 69.4% (95% CI 56?C83%); median survival 24.8 and 28.9?months. Combination chemotherapy produced more hematological toxicity without relevant differences in nonhematological toxicities.

Conclusions

The 4-drug regimen deserves further assessment in resectable pancreatic cancer.     

Intraoperative DTI and brain mapping for surgery of neoplasm of the motor cortex and the corticospinal tract: our protocol and series in BrainSUITE

We report our preliminary series of patients treated for lesions involving the motor cortex and the corticospinal tract in BrainSuite, with intraoperative MRI, tractography and "neuronavigated" electrophysiological cortical and subcortical mapping. An exact localization of the cortical and subcortical functional areas is mandatory for executing surgery of intra-parenchymal neoplasm involving the motor cortex and the corticospinal tract. Nowadays modern technology offers a variety of tools to reduce as much as possible postoperative deficits during surgery of cerebral eloquent areas. From December 2008 and June 2010, 18 patients underwent functional surgery, for neoplasm involving the motor cortex and/or the subcortical pathway, in BrainSuite. Our preliminary series include 14 gliomas and 4 metastases; Table 1 summarizes all of the data. We included in this series patients with complete removal of lesions of eloquent areas with an average distance from the corticospinal tract of 4 mm. Six neoplasms were considered in contact and/or involving the motor cortex, while in 18 cases (100%) the tumour involved eloquent areas concerning the corticospinal tract. All of the patients underwent complete removal of the lesion as subsequently demonstrated by intraoperative postsurgical MRI. Our series highlights the good integration and the high compatibility between BrainSUITE with 1.5 T intraoperative magnetic field and neurophysiological monitoring. We strongly believe that intraoperative MRI with DTI allows us to treat complex surgery tumours that without its auxilium we would not be able to deal with.     

Paraurethral leiomyoma

Paraurethral leiomyoma is a rare, benign, hormone-dependent neoplasm of mesenchymal origin affecting women. The clinical evidence varies, but it tends to be asymptomatic or associated with the sensation of a foreign body; urinary symptoms are rarely described. The distinction among urethral, paraurethral, and anterior vaginal wall leiomyoma can be very difficult owing to their anatomic proximity. Excision of the mass is the recommended treatment, and the diagnosis is confirmed by the pathologic finding to rule out the presence of a sarcoma. A case of paraurethral leiomyoma associated with dysuria, dyspareunia, and obstructive voiding symptoms is reported.     

Complete Pathologic Response after Combined Modality Treatment for Rectal Cancer and Long-Term Survival: A Meta-Analysis

Background

Complete pathologic response (CPR) after neoadjuvant chemoradiotherapy (combined modality treatment, CMT) for rectal cancer seems associated with improved survival compared to partial or no response (NPR). However, previous reports have been limited by small sample size and single-institution design.

Methods

A systematic literature review was conducted to detect studies comparing long-term results of patients with CPR and NPR after CMT for rectal cancer. Variables were pooled only if evaluated by 3 or more studies. Study end points included rates of CPR, local recurrence (LR), distant recurrence (DR), 5-year overall survival (OS), and disease-free survival (DFS).

Results

Twelve studies (1,913 patients) with rectal cancer treated with CMT were included. CPR was observed in 300 patients (15.6%). CPR and NPR patient groups were similar with respect to age, sex, tumor size, distance of tumor from the anus, and stage of disease before treatment. Median follow-up ranged from 23 to 46?months. CPR patients had lower rates of LR [0.7% vs. 2.6%; odds ratio (OR) 0.45, 95% confidence interval (CI) 0.22?C0.90, P?=?0.03], DR (5.3% vs. 24.1%; OR 0.15, 95% CI 0.07?C0.31, P?=?0.0001), and simultaneous LR?+?DR (0.7% vs. 4.8%; OR 0.32, 95% CI 0.13?C0.79, P?=?0.01). OS was 92.9% for CPR versus 73.4% for NPR (OR 3.6, 95% CI 1.84?C7.22, P?=?0.002), and DFS was 86.9% versus 63.9% (OR 3.53, 95% CI 1.62?C7.72, P?=?0.002).

Conclusions

CPR after CMT for rectal cancer is associated with improved local and distal control as well as better OS and DFS.