Circulating nucleosomes and response to chemotherapy: an in vitro,in vivo and clinical study on cervical cancer patients

It is known that cell-free DNA circulates in plasma/serum of patients with cancer and that part of this DNA circulates as nucleosomes that can be quantified by ELISA. We analyzed the effect of tumor and chemotherapy upon the levels of nucleosomes in vitro, in vivo and in cervical cancer patients. The levels of nucleosomes pre- and post-treatment were correlated with response in 11 patients receiving chemotherapy. Nucleosomes were determined in nude mice treated with or without cisplatin and carrying tumors generated with HeLa cells, and in the cell lysate and supernatant of HeLa cells exposed to cisplatin in culture. In addition, nucleosomes were determined at different time points in patients and in rats receiving chemotherapy. Nucleosomes were higher in patients that controls (1,760 vs. 601, p = 0.0001). After 24 hr of treatment with oxaliplatin and gemcitabine, the levels decreased in 6 patients of whom 5 had response. Nucleosome levels differed between mice xenografted and not xenografted (765 vs. 378, p = 0.001) and between xenografted treated with or without cisplatin (650 vs. 765, p = 0.010), but not in tumor-free animals treated and untreated with cisplatin (378 vs. 379, p = 0.99). In vitro, nucleosomes reached at peak 8 hr in cell lysates to decrease thereafter, whereas in supernatant, levels continued to increase up to 24 hr. Serial determination of nucleosomes in patients showed a rise within 6-12 hr and then a reduction to below the basal at 24 hr. In rats, nucleosomes had no major changes in those receiving oxaliplatin or the triple combination of cisplatin, gemcitabine and paclitaxel as compared to untreated controls. An overdose of this triple combination produced a transient elevation of almost 1,000 AU over the basal. Our results demonstrate that most of circulating nucleosomes originate from the tumor and that chemotherapy produces an early rise most likely due to tumor apoptosis and that nucleosomes are rapidly cleared from circulation. On the contrary, chemotherapy within the therapeutic range of doses has no effect on nucleosome levels in healthy mice and rats. This data suggests that the determination of circulating nucleosomes pre- and post-treatment could be a useful test to predict response to chemotherapy in cancer patients.     

The cortical silent period is shortened in migraine with aura

OBJECTIVES: Central neuronal hyperexcitability may be the physiological disturbance that predisposes subjects to migraine attacks. To test this hypothesis, we studied the cortical stimulation silent period (CSSP) elicited by transcranial magnetic stimulation (TMS), which is in part a measure of central inhibition of motor pathways in migraine with aura (MwA) patients and normal controls. METHODS: In nine MwA patients (mean age 35.9 +/- 7) and 9 controls (mean age 37.6 +/- 7), we carried out transcranial stimulation using a 95 mm circular coil and Caldwell MES 10 stimulator to determine resting motor threshold (MT) for bilateral FDI muscles. All subjects performed isometric voluntary contraction of bilateral FDI maintained at 20% of maximal effort, during which we measured bilateral CSSP at (i) the stimulus intensity (SI) determined for the MT and (ii) an SI of 1.5 x MT. RESULTS: Although the mean MT was higher in MwA compared with controls (63.1 +/- 14.4 vs 58.1 +/- 8.9), the difference was not significant. At an SI of 1.5 x MT the mean CSSP did not differ between the groups (MwA 141.7 +/- 31.9 vs controls 162.4 +/- 36.6). At the SI of the MT, however, the CSSP was shorter in MwA patients than in controls (62.9 +/- 27.3 vs 106.3 +/- 19.6, p = 0.001). There was an inverse correlation between the duration of CSSP and an increased frequency of headache (p = 0.02). CONCLUSIONS: The shortened CSSP that we measured in MWA patients compared to normal with low intensity magnetic stimulation suggests reduced central inhibition resulting in increased excitability of cortical neurons in migraine subjects. The association of CSSP reduction with increased frequency of migraine is further suggestive that brain excitability is the basis of susceptibility to migraine attacks.     

Vesical instillations of hyaluronic acid to reduce the acute vesical toxicity caused by high-dose brachytherapy do not affect the survival: a five-year follow-up study

Objective  

To determine whether the intravesical use of hyaluronic acid (HA) reduces acute and late vesical toxicity induced by radiotherapy.     

Synthesis, characterisation, and antineoplastic cytotoxicity of hybrid naphthohydroquinone–nucleic base mimic derivatives

From a partially degraded Diels–Alder adduct of α-myrcene and 1,4-benzoquinone, several model compounds belonging to a new series of 1,4-naphthohydroquinone derivatives have been prepared. Phenyl, pyridyl, imidazolyl and some nucleic base mimic heterocycles have been attached to the naphthohydroquinone system through linkers of different size and type, leading to potentially antineoplastic hybrid structures. The new compounds have been evaluated in vitro for their cytotoxicity against cultured human cancer cells of A-549 lung carcinoma, HT-29 colon adenocarcinoma and MDA-MB-231 breast carcinoma. GI₅₀ values ranged in the μM level.     

Control del embarazo y manejo intraparto en la enfermedad de McArdle

We describe the pregnancy course and labor in a woman with myophosphorylase deficiency (McArdle’s disease or glycogen storage disease type V). McArdle’s disease is an uncommon hereditary disorder characterized by symptoms of muscular fatigue and pain, as well as by muscle cramps during heavy and continuos exercise. We feared that the increase in muscular effort during labor might complicate delivery, necessitating cesarean section.