Constitutive activation of MAPK cascade in acute quadriplegic myopathy

Acute quadriplegic myopathy (AQM; also called "critical illness myopathy") shows acute muscle wasting and weakness and is experienced by some patients with severe systemic illness, often associated with administration of corticosteroids and/or neuroblocking agents. Key aspects of AQM include muscle atrophy and myofilament loss. Although these features are shared with neurogenic atrophy, myogenic atrophy in AQM appears mechanistically distinct from neurogenic atrophy. Using muscle biopsies from AQM, neurogenic atrophy, and normal controls, we show that both myogenic and neurogenic atrophy share induction of myofiber-specific ubiquitin/proteosome pathways (eg, atrogin-1). However, AQM patient muscle showed a specific strong induction of transforming growth factor (TGF)-beta/MAPK pathways. Atrophic AQM myofibers showed coexpression of TGF-beta receptors, p38 MAPK, c-jun, and c-myc, including phosphorylated active forms, and these same fibers showed apoptotic features. Our data suggest a model of AQM pathogenesis in which stress stimuli (sepsis, corticosteroids, pH imbalance, osmotic imbalance) converge on the TGF-beta pathway in myofibers. The acute stimulation of the TGF-beta/MAPK pathway, coupled with the inactivity-induced atrogin-1/proteosome pathway, leads to the acute muscle loss seen in AQM patients.     

Malignant germ cell tumors in childhood: results of the first Italian cooperative study "TCG 91"

BACKGROUND AND AIMS: About 20% of patients with germ cell tumor (GCT) are still resistant to therapy. To investigate which features are present in resistant patients, a multicenter study on GCT in children was undertaken to correlate clinical and laboratory parameters with the outcome. METHODS: Patients aged less than 16 years, with histologically proven extracranial GCT were included. RESULTS: Ninety-five patients (median age 33 months, 45 males) were eligible. The site of the primary tumor was gonadal in 59, extragonadal in 36. The stage was I in 39; II in 5; IIIa (microscopic residue) in 7; IIIb (macroscopic residue) in 16; IIIc (unresectable) in 13; IV in 15. The treatment was surgery alone in 31; surgery plus radiotherapy in 1; chemotherapy +/- surgery in 63. Post-chemotherapy resection in 19 (10 complete, 9 partial). The chemotherapy regimen was carboplatin 400 mg/m2/day on days 1, 2; etoposide 150 mg/m2/day on days 1, 2; ifosfamide 1,500 mg/m2/day on days 21, 22; dactinomycin 1.5 mg/m2/day on day 21; vincristine 1.5 mg/m2/day on day 21. Three patients died because of toxicity and two non-responders (to primary chemotherapy), died of progression; among the remaining 90 patients 20 relapsed, 9 are in second remission, 2 are alive with disease, and 9 died of disease progression (one from progression and intracranial hemorrhage). Overall survival was 82.7% and event-free survival: 71.5%. Survival according to: (a) site: testis: 100%; ovary: 88%; sacrococcyx: 69.6%; other sites: 33.3% (P < 0.001); (b) stage: I and II: 100%; IIIa: 83.3%; IIIb: 84.6%; IIIc: 60.6%; IV: 53.2% (P < 0.001); (c) AFP levels: normal: 85.5%; 42-9,470 ng/ml: 84.6%; >/=10,000 ng/ml: 58.7% (P = 0.02). All the pts who had complete resection of the primary tumor at diagnosis or at delayed surgery, remained in remission. CONCLUSIONS: Multivariate analysis showed that the primary site of tumor was the only independent prognostic factor for survival and EFS.     

Low-molecular-weight heparin and cancer survival: review of the literature and pooled analysis of 1,726 patients treated for at least three months

BACKGROUND: Heparin has been the main subject of intensive investigation and clinical use because of its therapeutic anticoagulant properties. It also exhibits many other biological activities, and it was claimed that it shows a beneficial effect on cancer spreading. Searching for papers investigating the effect of low-molecular-weight heparin (LMWH) on cancer mortality we found clinical trials and meta-analyses which showed a reduction in the mortality rate in cancer patients. However, the biological rationale of this effect for a short treatment with LMWH remains unclear. We wanted to check if similar results were achieved in cancer patients treated with LMWH for a longer period of time. AIM: To evaluate the effect on cancer mortality of a 3-month treatment with LMWH by performing a meta-analysis of published studies comparing LMWH and oral anticoagulants (OA) in the prevention of recurrent venous thromboembolism (VTE). MATERIALS AND METHODS: Computerized searches of Medline and Embase were performed; clinical trials were also located through colleagues and hand scanning of meeting proceedings. Eligibility of the studies and extraction of data were performed by two authors using a standard form. The meta-analysis was performed assuming a fixed-effect model. RESULTS: Eight studies were identified that fulfilled our predefined criteria for a total of 1,726 patients. After a mean of 8.6 months of follow-up, 327 patients had died of cancer, 160 in the LMWH group and 167 in the OA control group (OR 0.95, 95% CI 0.73-1.23; z = 0.42; p = 0.67). Considering cancer mortality in 948 cancer patients the figures were 160/472 in the LMWH group and 167/476 in the OA control group (OR 0.96, 95% CI 0.73-1.25; z = 0.33; p = 0.74). CONCLUSIONS: In 1,726 patients randomized to receive a long-term course of at least 3 months of LMWH or OA for the treatment of VTE, no effect on cancer mortality was found.     

Biologic and therapeutic role of HER2 in cancer

Overexpression of the human epidermal growth factor-2 (HER2) oncogene in human breast carcinomas has been associated with a more aggressive course of disease. The reason for this association is still unclear, although it has been suggested to rest in increased proliferation, vessel formation, and/or invasiveness. Alternatively, prognosis may not be directly related to the presence of the oncoprotein on the cell membrane, but instead to the breast carcinoma subset identified by HER2 overexpression and characterized by a peculiar gene expression profile. HER2 has also been associated with sensitivity to anthracyclins and resistance to endocrine therapy, suggesting that tyrosine kinase receptor and hormone receptor pathways represent two major proliferation pathways exclusively active in breast carcinomas, one sensitive to chemotherapeutic drugs and the other to antiestrogens. HER2 currently represents one of the most appropriate targets for specific therapy. Indeed, trastuzumab, a monoclonal antibody directed against the extracellular domain of HER2, is therapeutically active in HER2-positive breast carcinomas. However, a consistent number of HER2-positive tumors is not responsive to HER2-driven therapy, indicating the need for a better understanding of the mechanism of action of this new biological drug in vivo. While preclinical studies suggest antibody-dependent cell cytotoxicity as the major mechanism, determination of NK activity at the time of treatment remains mandatory, especially in patients treated with immunosuppressive drugs. The efficacy of prophylactic vaccination has been fully demonstrated in preclinical models, whereas ongoing studies of active immunotherapy using a variety of vaccination regimens against HER2 in tumor-bearing mice and patients have met with only moderate success.     

Multiple Pathways Analysis of Brain Functional Networks from EEG Signals: An Application to Real Data

In the present study, we propose a theoretical graph procedure to investigate multiple pathways in brain functional networks. By taking into account all the possible paths consisting of h links between the nodes pairs of the network, we measured the global network redundancy R _h as the number of parallel paths and the global network permeability P _h as the probability to get connected. We used this procedure to investigate the structural and dynamical changes in the cortical networks estimated from a dataset of high-resolution EEG signals in a group of spinal cord injured (SCI) patients during the attempt of foot movement. In the light of a statistical contrast with a healthy population, the permeability index P _h of the SCI networks increased significantly (P < 0.01) in the Theta frequency band (3–6 Hz) for distances h ranging from 2 to 4. On the contrary, no significant differences were found between the two populations for the redundancy index R _h . The most significant changes in the brain functional network of SCI patients occurred mainly in the lower spectral contents. These changes were related to an improved propagation of communication between the closest cortical areas rather than to a different level of redundancy. This evidence strengthens the hypothesis of the need for a higher functional interaction among the closest ROIs as a mechanism to compensate the lack of feedback from the peripheral nerves to the sensomotor areas.