DNA damage signaling mediates the functional antagonism between replicative senescence and terminal muscle differentiation.

The molecular determinants of muscle progenitor impairment to regenerate aged muscles are currently unclear. We show that, in a mouse model of replicative senescence, decline in muscle satellite cell-mediated regeneration coincides with activation of DNA damage response (DDR) and impaired ability to differentiate into myotubes. Inhibition of DDR restored satellite cell differentiation ability. Moreover, in replicative human senescent fibroblasts, DDR precluded MYOD-mediated activation of the myogenic program. A DDR-resistant MYOD mutant could overcome this barrier by resuming cell cycle progression. Likewise, DDR inhibition could also restore MYOD's ability to activate the myogenic program in human senescent fibroblasts. Of note, we found that cell cycle progression is necessary for the DDR-resistant MYOD mutant to reverse senescence-mediated inhibition of the myogenic program. These data provide the first evidence of DDR-mediated functional antagonism between senescence and MYOD-activated gene expression and indicate a previously unrecognized requirement of cell cycle progression for the activation of the myogenic program.

Evidence for faulting and fluid-driven earthquake processes from seismic attenuation variations beneath metropolitan Los Angeles.

Seismicity in the Los Angeles metropolitan area has been primarily attributed to the regional stress loading. Below the urban areas, earthquake sequences have occurred over time showing migration off the faults and providing evidence that secondary processes may be involved in their evolution. Combining high-frequency seismic attenuation with other geophysical observations is a powerful tool for understanding which Earth properties distinguish regions with ongoing seismicity. We develop the first high-resolution 3D seismic attenuation models across the region east of downtown Los Angeles using 5,600 three-component seismograms from local earthquakes recorded by a dense seismic array. We present frequency-dependent peak delay and coda-attenuation tomography as proxies for seismic scattering and absorption, respectively. The scattering models show high sensitivity to the seismicity along some of the major faults, such as the Cucamonga fault and the San Jacinto fault zone, while a channel of low scattering in the basement extends from near the San Andreas fault westward. In the vicinity of the Fontana seismic sequence, high absorption, low scattering, and seismicity migration across a fault network suggest fluid-driven processes. Our attenuation and fault network imaging characterize near-fault zones and rock-fluid properties beneath the study area for future improvements in seismic hazard evaluation.

Palonosetron for the prevention of chemotherapy-induced nausea and vomiting in glioblastoma patients treated with temozolomide: a phase II study.

PURPOSE: Chemotherapy-induced nausea and vomiting (CINV) is a side effect related to administration of the adjuvant temozolomide (TMZ) in patients affected by glioblastoma. After chemoradiotherapy, adjuvant TMZ is administered as an oral multiple-day regimen, and TMZ-associated CINV may interfere with the continuation of chemotherapy, with potentially negative consequences on clinical efficacy. The aim of the present study was to investigate the efficacy of palonosetron for prevention of CINV-induced by adjuvant TMZ. METHODS: From March 2007 to August 2008, 33 patients with confirmed glioblastoma and eligible for adjuvant treatment with TMZ were enrolled in the study. All patients with responding or stable disease after concomitant radiotherapy plus daily TMZ (75 mg/m(2)) received a single i.v. bolus 0.25 mg of palonosetron 30 min before the beginning of adjuvant TMZ (150-200 mg/m(2)/day for five consecutive days every 4 weeks). The primary endpoint was the percentage of patients with complete response (CR), defined as no emetic episodes and no rescue medication during the overall phase (0-168 h). Secondary endpoints included CR during the 0-120 h and 0-168 h phases and complete control (CC; CR and no more than mild nausea) during the 0-120 h, 120-168 h, and 0-168 h phases. RESULTS: Thirty-three patients were enrolled in the study (median age 57.6 years, 23 male and 10 female, median Karnofsky Performance Status = 80). Each patient was receiving fixed doses of dexamethasone (range 2-8 mg/day). CR in the 0-120 h, 120-168 h, and 0-168 h phases was seen in 91% of patients. CC was observed in 88%, 91%, and 88% of cases during the 0-120 h, 120-168 h, and 0-168 h phases, respectively. Anti-emetic prophylaxis with palonosetron was well tolerated and the most frequent adverse event was grade 1-2 headache reported by seven patients (21%). CONCLUSION: A single dose of palonosetron before the initiation of multiple oral doses of TMZ, in patients on treatment with steady doses of dexamethasone, provides a high protection against CINV throughout the overall phase (0-168 h). The pharmacological profile of palonosetron, compared to first-generation 5-HT3 receptor antagonists, may have an impact on its clinical efficacy.

A facial reconstruction method based on new mesh deformation techniques.

This article presents a new numerical method for facial reconstruction. The problem is the following: given a dry skull, reconstruct a virtual face that would help in the identification of the subject. The approach combines classical features as the use of a skulls/faces database and more original aspects: (1) an original shape matching method is used to link the unknown skull to the database templates; (2) the final face is seen as an elastic 3D mask that is deformed and adapted onto the unknown skull. In this method, the skull is considered as a whole surface and not restricted to some anatomical landmarks, allowing a dense description of the skull/face relationship. Also, the approach is fully automated. Various results are presented to show its efficiency.

Nail disorders in a woman treated with ixabepilone for metastatic breast cancer.

Ixabepilone (Ix) (BMS-247550) is a potent member of a new class of microtubule-stabilizing cytotoxic agents known as epothilones. In pre-clinical studies, Ix has shown anticancer activity against several cancer types, including paclitaxel-resistant models, both in vitro and in vivo. The major toxicities associated with Ix are myelosuppression, sensory neuropathy and neutropenia. Other minor side-effects include asthenia/fatigue, stomatitis, anorexia, alopecia, skin reaction, hypersensitivity reactions and a fluid-retention syndrome. Although Ix is functionally correlated to taxanes, no previous evidence exists regarding Ix-related nail disorders. Here, we report a case of a 59-year-old woman treated with Ix at 40 mg/m2 day 1 q 21 days who, after 8 cycles of therapy, developed onycholysis and subungual hemorrhagic bullas in the fingernails.

Alfa-epoietin and anaemia in gynaecological cancer.

The incidence and severity of anaemia in gynaecological cancer patients depends on several factors including age, histology and tumor stage, site of neoplasm and treatment. At present, two principal opinions are available for the management of chronic anaemia in cancer patients: blood transfusions and treatment with recombinant human Erythropoietin (rHuEPO). Clinical studies showed that rHuEPO can ameliorate chronic and chemotherapy-induced anaemia and reduce transfusions in patients with various malignant diseases. In this review we discuss the role of alfa-epoetin in the management of gynaecological and breast cancers.

Epirubicin plus docetaxel in metastatic breast cancer: escalating dose does not improve efficacy. A phase II study.

BACKGROUND: The combination of anthracyclines and docetaxel have demonstrated a significant activity in metastatic breast cancer (MBC) as first-line chemotherapy. In a previous multicenter phase I study, we recommended two schedules of epirubicin-docetaxel combination for MBC: 1) epirubicin 75 mg/m2, docetaxel 80 mg/m2 every 3 weeks without G-CSF; 2) epirubicin 90 mg/m2 plus docetaxel 90 mg/m2 every 3 weeks, with G-CSF support. PATIENTS AND METHODS: Twenty-five advanced breast cancer patients were treated with epirubicin 90 mg/m2 plus docetaxel 90 mg/m2 every 3 weeks, with prophylactic G-CSF. RESULTS: The main toxicity was grade 3-4 neutropenia (41% of cycles) despite the use of G-CSF; febrile neutropenia was observed in 14% of cycles necessitating a dose reduction of both drugs in 30% of patients. Response was observed in 79% of patients: 21% complete responses and 58% partial responses. The median response duration was 10 months (range: 3-16). The median time to progression was 11 months. The overall 3-year survival was 49.7%. CONCLUSION: The antitumor activity observed in this series was comparable with that seen in other studies of taxane/anthracycline combinations. The degree of myelosuppression was severe, even though G-CSF was administered as a prophylactic. We recommend a lower dose of both drugs as reported by other authors.

Pegylated liposomal doxorubicin as third-line chemotherapy in patients with metastatic transitional cell carcinoma of urothelial tract: results of a phase II study.

Until the recent approval of vinflunine, no standard second-line chemotherapy existed for advanced transitional cell carcinoma (TCC). Few data exist about third-line chemotherapy for metastatic disease. Although administered in up-front regimens, anthracyclines were never evaluated beyond second-line treatment. This study assessed the activity of pegylated liposomal doxorubicin (PLD) in patients with advanced TCC previously treated with two chemotherapy regimens. From May 2005 to June 2009, 23 patients with metastatic TCC were recruited: median age was 62 years (49-76 years) with a median ECOG PS of 1. Patients received PLD 35 mg/m(2) every 21 days. All patients were evaluable for efficacy and toxicity. No patient showed complete response. Three patients (13 %) had partial response; seven patients (30 %) showed stable disease for a disease control rate of 43 %. The median time to progression (TTP) was 4.1 months with a median survival time (MST) of 6.3 months. Treatment was well tolerated: no patient developed grade 4 toxicities. This is the first study which evaluated the role of anthracyclines as third-line chemotherapy in metastatic TCC. Despite its manageable profile of toxicity, PLD showed modest activity. Beyond second-line chemotherapy, supportive care still represents the best therapeutic option for patients with metastatic TCC.