Post-diagnosis serum 25-hydroxyvitamin D concentrations in women treated for breast cancer participating in a lifestyle trial in Italy.

OBJECTIVE: To report cross-sectionally serum levels of 25-hydroxyvitamin D [25(OH)D] in women living in Italy within 12 months from breast cancer (BC) diagnosis. METHODS: Baseline data were obtained from 394 women diagnosed with primary BC, enrolled from 2016 to 2019 in a lifestyle trial conducted in Italy. Subjects' characteristics were compared between two 25(OH)D concentrations (hypovitaminosis D<20 and ≥20 ng/mL) with the Chi-squared test or Fisher's exact test for small-expected counts. Using multiple logistic regression-adjusted models, we estimated odds ratios (ORs) of hypovitaminosis D with 95% confidence intervals (CIs) in the total sample and in the unsupplemented subgroup. RESULTS: Hypovitaminosis D was found in 39% of all subjects, 60% in unsupplemented subjects, and 10% in supplemented subjects. Increasing ORs of hypovitaminosis D were found with increasing body mass index, 25-30, >30, and ≥35 versus <25 kg/m2 (ORs: 2.50, 4.64, and 5.81, respectively, in the total cohort and ORs: 2.68, 5.38, and 7.08 in the unsupplemented); living in the most southern Italian region (OR 2.50, 95%CI 1.22-5.13); and with hypertriglyceridemia (OR 2.46; 95%CI 1.16-5.22), chemotherapy history (OR 1.86, 95%CI 1.03-3.38), and inversely with anti-estrogenic therapy (OR 0.43, 95%CI 0.24-0.75) in the total sample. CONCLUSIONS: Hypovitaminosis D in women recently diagnosed with BC and participating in a lifestyle trial in Italy was widespread and highest with obesity, hypertriglyceridemia, and chemotherapy use. Considering that hypovitaminosis D is a risk factor for lower efficacy of bone density treatments and possibly BC mortality, our results suggest the need to promptly address and treat vitamin D deficiency.

Saccorhiza polyschides used to synthesize gold and silver nanoparticles with enhanced antiproliferative and immunostimulant activity.

Over the last years, there has been an increasing trend towards the use of environmentally friendly processes to synthesize nanomaterials. In the case of nanomedicine, the use of bionanofactories with associated biological properties, such as seaweed, has emerged as a promising field of work due to the possibility they open for both the preservation of those properties in the nanomaterials synthesized and/or the reduction of their toxicity. In the present study, gold (Au@SP) and silver (Ag@SP) nanoparticles were synthesized using an aqueous extract of Saccorhiza polyschides (SP). Several techniques showed that the nanoparticles formed were spherical and stable, with mean diameters of 14 ± 2 nm for Au@SP and 15 ± 3 nm for Ag@SP. The composition of the biomolecules in the extract and the nanoparticles were also analyzed. The analyses performed indicate that the extract acts as a protective medium, with the particles embedded in it preventing aggregation and coalescence. Au@SP and Ag@SP showed superior immunostimulant and antiproliferative activity on immune and tumor cells, respectively, to that of the SP extract. Moreover, the nanoparticles were able to modulate the release of reactive oxygen species depending on the concentration. Hence, both nanoparticles have a significant therapeutic potential for the treatment of cancer or in immunostimulant therapy.

Combination of sunitinib, cetuximab and irradiation in an orthotopic head and neck cancer model.

BACKGROUND: Recent preclinical and clinical studies indicate beneficial effects from combining radiotherapy with either anti-angiogenic drugs or anti-epidermal growth factor receptor (EGFR)-targeting agent. To investigate the effect of combining these approaches, we evaluated in vivo the antitumor efficacy of the anti-angiogenic compound sunitinib, an oral, multi-targeted tyrosine kinase inhibitor that inhibits among others vascular endothelial growth factor (VEGF) receptors-1, -2 and -3, cetuximab, a mAb targeting the EGFR, and irradiation (RT) given alone and in combination. MATERIALS AND METHODS: Investigations were carried out using a VEGF-secreting human head and neck tumor cell line, CAL33, with a high EGFR content, growing as orthotopic xenografts in nude mice. Three days after tumor cell injection, sunitinib (20 mg/kg, p.o.), cetuximab (1 mg/kg, i.p.), both 5 days/week seven doses, and RT (6 Gy, 3 days/week, four doses) were administered alone and in combination during 9 days. RESULTS: Concomitant administration of drugs produced a marked and significant supra-additive decrease, and the addition of RT completely abolished tumor growth. The drug association markedly reduced tumor cell proliferation (Ki67) and the number of the vessels, but enhanced cell differentiation. CONCLUSION: The efficacy of this combination of sunitinib, cetuximab and RT may be of clinical importance in the management of head and neck cancer patients.

[Painful perineum in all its forms. Contribution of manual medicine and osteopathy. Clinical study]. / Le périnée douloureux sous toutes ses formes. Apport de la médecine manuelle et ostéopathie. Etude clinique.

No satisfactory therapy has yet been found to relieve many chronic pelviperineal pains such as Dyspareunia, Vulvodynia, Coccygodynia and other various pelvic pains, although these can be highly disruptive in everyday life. They may be brought on by an osteo-myo-fascial disorder, often undetected despite the possibility to effectively treat, this condition using manual medicine in the gynaecologist's office. A framed clinical examination protocol as well as a therapeutic one are offered in this novel approach still rarely implemented in gynaecology. Such treatment is documented in six typical clinical cases and a global study on 86 patients with disruptive chronic pelviperineal pain, showing 71% satisfactory results following two manual medicine sessions. These very encouraging results need to be confirmed on a larger scale in order to establish an appropriate teaching protocol.

Chronopharmacokinetics of oral tegafur and uracil in colorectal cancer patients.

Uracil-Ftorafur (UFT) combines the 5-fluorouracil (FU) prodrug tegafur with uracil (at a 1:4 molar ratio), which is a competitive inhibitor of dihydropyrimidine dehydrogenase (DPD), the limiting enzyme of FU catabolism. As a result, sustained FU concentrations are obtained in both plasma and tumor. UFT is an effective alternative to intravenous FU-Leucovorin (LV) in metastatic and adjuvant colorectal cancer treatment. A circadian rhythm for DPD activity has been shown in both human and animal studies, with consequences on FU plasma concentrations in patients receiving FU as a continuous infusion. The chronopharmacokinetics of FU has stimulated clinical trials of chronomodulated delivery schedules for floxuridine and FU infusions, suggesting that such schedules may improve the fluoropyrimidine therapeutic index. Molecular mechanisms responsible for the circadian dependence of FU pharmacodynamics include circadian rhythms in thymidylate synthase activity and DNA synthesis, as recently reported. Chronopharmacology of FU prodrugs is poorly documented. Recently, a feasibility study of chronomodulated administration of the FU oral prodrug capecitabine was reported. To our knowledge, the only study reporting on the time dependency of UFT pharmacokinetics is a phase I study by Muggia et al.

MRI indirect stereotactic targeting for deep brain stimulation in Parkinson's disease.

AIM: Stereotactic localisation of brain targets for functional neurosurgery might be obtained with different neuroimaging sources. Magnetic resonance (MR) might be of particular interest for its high definition of the various brain structures; unfortunately, magnetic field distortion and inaccuracy in imaging reproduction constrain the use of MRI in stereotactic surgery. METHODS: We present an experimental work devoted to the utilization of MRI in the targeting of the subthalamic nucleus for deep brain stimulation (DBS) in Parkinsonian patients. RESULTS: Experimental data were obtained after PVC phantom and fixed human brain measurements of the stereotactic coordinates of specific basal ganglia structures. Intrinsic and external sources of error and imaging distortion have been carefully corrected. Afterwards, 36 patients, operated for DBS in the subthalamus for Parkinson's disease (PD), have been investigated. MRI targeting proved to be clinically successful; comparing anatomical and neurophysiological findings, MRI targeting scattered from the neurophysiological targeting in a minority of cases. CONCLUSION: MRI targeting proved to be reliable for functional stereotactic surgery, pending careful and adequate quality control of the distortion and of the sources of error.

Deep brain stimulation for the treatment of Parkinson's disease: the experience of the Neurosurgical Department in Monza.

deep brain stimulation is a widely accepted surgical therapy for the symptomatic treatment of advanced parkinson's disease; high frequency chronic stimulation of the subthalamic nucleus proved its efficacy to control the major motor symptoms. In the neurosurgical department of Monza we treated 72 parkinsonian patients (November 1998-January 2003). One year follow-up results are: decrease of tremor 90%, hypertonous 56%, bradykinesia 70%, voice impairment amelioration 30%, mean total daily L-dopa intake reduced 58%. Freezing and balance did not ameliorate, some voice impairment and psychic derangement have been observed. Major surgical complications were: haemorrage (1 case - transient hemiparesis), infections (2 cases), pulmonary embolisation (1 case). To optimise the surgical results, careful clinical and instrumental selection of the patients are mandatory before surgery.

Cannabinoid receptor activation and elevated cyclic AMP reduce glutamate neurotoxicity.

Cannabinoid receptor activation in vivo reduces ischemic injury, a phenomenon that has not been successfully reproduced in vitro. Because cyclic adenosine monophosphate (cAMP) levels are radically elevated during ischemic reperfusion, but cannabinoid receptor activation reduces cAMP levels, we hypothesized that cannabinoids might prevent in vitro glutamate toxicity if reperfusion was simulated by cAMP supplementation after glutamate removal. Although neuronal cultures were unaffected by the single addition of either cannabinoid or dibutyryl cAMP (dbcAMP), glutamate toxicity was reduced by 20% when cannabinoid was present during glutamate exposure and either dbcAMP or forskolin was added after glutamate removal. Further studies revealed that cannabinoid receptor activation reduces glutamate toxicity by attenuating calcium influx through N- and P/Q-type calcium channels. The effect of glutamate exposure on neuronal cAMP levels was also examined. Glutamate exposure significantly reduced neuronal cAMP levels, although suppression was even greater when cannabinoid was present. Because neurological outcome after ischemia is poor when cAMP levels during reperfusion are low, it is hypothesized that cAMP elevation after glutamate exposure may offset excitotoxic and/or cannabinoid receptor-induced cAMP depletion. Cannabinoids protect against ischemic injury in vivo, but only reduce toxicity in vitro when cAMP levels are elevated, possibly suggesting that cAMP elevation during reperfusion reduces brain injury by off-setting the effect of Gi/o protein-coupled systems on adenylate cyclase.

Deletion of amino acid residues 18-75 inactivates the plasma membrane Ca2+ pump.

A mutant of the plasma membrane Ca2+ pump hPMCA4b(d18-75)(ct120) containing a deletion of the N-terminal amino acid residues 18-75 and lacking the C-terminal 120 amino acid residues was expressed in COS-1 cells. The deletion in the N-terminal region did not significantly affect the level of expression of the Ca2+ pump. Tryptic digestion of the hPMCA4b(d18-75)(ct120) mutant resulted in the appearance of the same fragments obtained by proteolysis of the hPMCA4b(ct120) enzyme, suggesting that deletion of residues 18-75 neither impeded the insertion in the membrane nor extensively affected the folding of the mutant protein. The functional competence of the hPMCA4b(d18-75)(ct120) enzyme was examined by measuring the Ca2+ transport and the Ca2+ ATPase activity of COS-1 cell microsomes expressing the mutant protein. Both tests proved the mutant to be inactive. Under conditions in which hPMCA4b(ct120) becomes phosphorylated, hPMCA4b(d18-75)(ct120) was incapable of reacting with ATP and Ca2+ to form the phosphoenzyme. Taken together these results suggest that the segment of amino acids 18-75 is essential for the activity of the plasma membrane Ca2+ pump.

Lipopolysaccharide modulation of eicosanoid and corticotrophin-releasing hormone release from rat hypothalamic explants and astrocyte cultures in vitro: evidence for the involvement of prostaglandin E2 but not prostaglandin F2 alpha and lack of effect of nerve growth factor.

Bacterial lipopolysaccharide (LPS) and prostaglandins (PG) E2 and F2 alpha are putative activators of the hypothalamo-pituitary-adrenal axis. Certain of the biological effects of LPS may be mediated by cytokines such as interleukin-1 beta (IL-1 beta), while IL-1 beta itself may operate via induction of the prostaglandins and/or nerve growth factor (NGF). As IL-1 beta stimulates the release of corticotrophin-releasing hormone (CRH) from acute rat hypothalamic explants directly, the effects of these substances on the release of CRH in vitro were investigated in short- and medium-term (20 and 60 min) incubations. The effect of LPS on the release of PGE2 and PGF2 alpha from these explants, as well as from cortical astrocyte cultures, was also studied. LPS did not modify the release of CRH, PGE2 or PGF2 alpha in 20-min incubations. In 60-min incubations, LPS stimulated the release of PGE2, whereas the release of CRH was weakly, but significantly, reduced; PGF2 alpha was not altered. PGE2 significantly stimulated CRH release in the 60-min but not in the 20-min experiments. This effect appeared to be selective for PGE2, since PGF2 alpha did not modify CRH release, alone or in combination. LPS also selectively released PGE2 but not PGF2 alpha from cortical astrocyte cultures after 24-h incubation. NGF had no effect on the release of explant CRH, regardless of the length of incubation.(ABSTRACT TRUNCATED AT 250 WORDS)

Regulation of human amnion cell growth and morphology by sera, plasma, and growth factors.

The requirements of human epithelial cells derived from the amnion membrane for serum factors were investigated. The growth promoting effects of human whole blood serum (WBS), platelet-poor defibrinogenated plasma, and plasma-derived serum (PDS) were examined in primary cultures of these ectodermal cells. The numbers of population doublings recorded after 10 days in the presence of 10% WBS, defibrinogenated plasma, or PDS were 2.3, 2.0 or 1.5, respectively. Although dialysis of sera or plasma had little effect on growth promotion, it markedly decreased the capacity of plasma to maintain cells in culture beyond 10 days. The differences in growth activities could not be attributed to the presence of anticoagulant in plasma and PDS or to the presence of excess calcium in PDS. Platelet lysates and purified platelet-derived growth factor had no effect on growth. Amnion cell growth was enhanced by epidermal growth factor (EGF) or hydrocortisone, but the glucocorticoid did not condition cells to respond to growth factors. Insulin and fibroblast growth factor singly or in combination had no effect on cell replication. Giant cell formation accompanied maintenance in hydrocortisone with defibrinogenated plasma and PDS. Discrete regions of dense population appeared in the presence of hydrocortisone, EGF, and undialyzed supplements.

Inhibition of growth of human breast cancer cell line MCF-7 by serum derived from calcium chloride-clotted plasma.

The growth of MCF-7 cells, established from a metastatic mammary carcinoma, and of HBL-100 cells, derived from a primary culture of human milk, was examined in medium supplemented with whole blood serum (WBS), defibrinogenated plasma, and plasma-derived serum (PDS). PDS obtained from platelet-poor plasma collected with the anticoagulant citrate phosphate dextrose and clotted by the addition of calcium chloride did not promote the growth of MCF-7 cells as well as did WBS or platelet-poor defibrinogenated plasma alone. Growth-inhibitory activity was observed when final cell densities in the presence of PDS combined with fetal bovine serum (FBS) were compared with those in control cultures maintained in FBS alone. The level of this activity in PDS varied among donors. Inhibition was not observed with HBL-100 cells. Calcium chloride did not induce inhibitory activity when added to WBS or defibrinogenated plasma, and platelet components did not alter the level of inhibition in PDS. However, platelet extracts did affect the expression of inhibition when added to plasma before clotting. Activity was diminished following dialysis of PDS, which suggested that inhibition stemmed from a small-molecular-weight factor for which expression depended on the mechanism of plasma coagulation.

Serum selenium and reticuloendothelial tumors.

Serum selenium levels were determined by neutron activation analysis on 59 patients with a variety of reticuloendothelial neoplasms. Correlations were attempted between the widely variable range in the serum concentrations of the trace element with the parameters employed in this study. Therapy, particularly less than six weeks initiation, produced elevations in the serum selenium levels.