Particle Path Correlations in a Phonon Bath

The path integral formalism is applied to derive the full partition function of a generalized Su-Schrieffer-Heeger Hamiltonian describing a particle motion in a bath of oscillators. The electronic correlations are computed versus temperature for some choices of oscillators energies. We study the perturbing effect of a time averaged particle path on the phonon subsystem deriving the relevant temperature dependent cumulant corrections to the harmonic partition function and free energy. The method has been applied to compute the total heat capacity up to room temeperature: a low temperature upturn in the heat capacity over temperature ratio points to a glassy like behavior ascribable to a time dependent electronic hopping with variable range in the linear chain.Comment: To be published in J.Phys.:Condensed Matte

Lattice dynamics effects on small polaron properties

This study details the conditions under which strong-coupling perturbation theory can be applied to the molecular crystal model, a fundamental theoretical tool for analysis of the polaron properties. I show that lattice dimensionality and intermolecular forces play a key role in imposing constraints on the applicability of the perturbative approach. The polaron effective mass has been computed in different regimes ranging from the fully antiadiabatic to the fully adiabatic. The polaron masses become essentially dimension independent for sufficiently strong intermolecular coupling strengths and converge to much lower values than those tradition-ally obtained in small-polaron theory. I find evidence for a self-trapping transition in a moderately adiabatic regime at an electron-phonon coupling value of .3. Our results point to a substantial independence of the self-trapping event on dimensionality.Comment: 8 pages, 5 figure

Melanocortin receptor agonist NDP-α-MSH improves cognitive deficits and microgliosis but not amyloidosis in advanced stages of AD progression in 5XFAD and 3xTg mice

Introduction: Alzheimer's disease (AD) is the most frequent cause of dementia and still lacks effective therapy. Clinical signs of AD include low levels of endogenous melanocortins (MCs) and previous studies have shown that treatment with MC analogs induces neuroprotection in the early stages of AD.Methods: We investigated the neuroprotective role of MCs in two transgenic mouse models of severe AD using 5 and 7 month-old (mo) 5XFAD mice and 9 and 12 mo 3xTg mice. These mice were subjected to a chronic stimulation of MC receptors (MCRs) with MC analogue Nle4-D-Phe7-alpha-melanocyte stimulating hormone (NDP-alpha-MSH, 340 mu g/kg, i.p.). Mouse behavior and ex-vivo histological and biochemical analyses were performed after 50 days of treatment.Results:Our analysis demonstrated an improvement in cognitive abilities of AD mice at late stage of AD progression. We also showed that these protective effects are associated with decreased levels of hyperphosphorylated Tau but not with A beta burden, that was unaffected in the hippocampus and in the cortex of AD mice. In addition, an age-dependent NDP effect on glial reactivity was observed only in 3xTg mice whereas a global downregulation of p38 mitogen-activated protein kinase was selectively observed in 7 mo 5XFAD and 14 mo 3xTg mice.Conclusion: Our results suggest that MCR stimulation by NDP-alpha-MSH could represent a promising therapeutic strategy in managing cognitive decline also at late stage of AD, whereas the effects on neuroinflammation may be restricted to specific stages of AD progression

Bioavailable testosterone linearly declines over a wide age spectrum in men and women from the Baltimore longitudinal study of aging

Background: Age-related changes in testosterone levels in older persons and especially in women have not been fully explored. The objective of this study was to describe age-related trajectories of total testosterone (TT), ammonium sulfate precipitation-measured bioavailable testosterone (mBT), and sex hormone-binding glycoprotein (SHBG) in men and women from the Baltimore Longitudinal Study of Aging, with special focus on the oldest adults. Methods: Participants included 788 White men and women aged 30-96 years with excellent representation of old and oldest old, who reported not taking medications known to interfere with testosterone. Longitudinal data were included when available. TT, mBT, and SHBG were assayed. Age-related trajectories of mBT were compared with those obtained using calculated bioavailable testosterone (cBT). Generalized least square models were performed to describe age-related trajectories of TT, mBT, and SHBG in men and women. Results: mBT linearly declines over the life span and even at older ages in both sexes. In men, TT remains quite stable until the age of 70 years and then declines at older ages, whereas in women TT progressively declines in premenopausal years and slightly increases at older ages. Differences in age-related trajectories between total and bioavailable testosterone are only partially explained by age changes in SHBG, whose levels increases at accelerated rates in old persons. Noteworthy, although mBT and cBT highly correlated with one another, mBT is a much stronger correlate of chronological age than cBT. Conclusion: In both men and women, mBT linearly declines over the life span and even at old ages. Its relationship with age-related phenotypes should be further investigated

Assessment of DNA Damage and Telomerase Activity in Exfoliated Urinary Cells as Sensitive and Noninvasive Biomarkers for Early Diagnosis of Bladder Cancer in Ex-Workers of a Rubber Tyres Industry

The aim of the present study was to identify sensitive and noninvasive biomarkers of early carcinogenic effect at target organ to use in biomonitoring studies of workers at risk for previous occupational exposure to potential carcinogens. Standard urine cytology (Papanicolaou staining test), comet assay, and quantitative telomerase repeat amplification protocol (TRAP) assay were performed in 159 ex-rubber workers employed in tyres production and 97 unexposed subjects. In TRAP positive cases, a second level analysis using FISH (Urovysion) was done. Cystoscopy results were available for 11 individuals whose 6 FISH/TRAP/comet positive showed in 3 cases a dysplastic condition confirmed by biopsy, 1 comet positive resulted in infiltrating UBC to the biopsy and with hyperplasia and slight dysplasia to the urinary cytology, 1 comet positive resulted in papillary superficial UBC to the biopsy, 1 FISH/TRAP positive showed a normal condition, and 2 TRAP positive showed in one case a phlogosis condition. The results evidenced good concordance of TRAP, comet, and FISH assays as early biomarkers of procarcinogenic effect confirmed by the dysplastic condition and UBC found by cystoscopy-biopsy analysis. The analysis of these markers in urine cells could be potentially more accurate than conventional cytology in monitoring workers exposed to mixture of bladder potential carcinogens

Phase II study of gemcitabine, doxorubicin and paclitaxel (GAT) as first-line chemotherapy for metastatic breast cancer: a translational research experience

BACKGROUND: Patients with metastatic breast cancer are frequently treated with anthracyclines and taxanes, which are among the most active agents in this disease. Gemcitabine is an interesting candidate for a three-drug combination because of its different mechanism of action and non-overlapping toxicity with respect to the other two drugs. We aimed to evaluate the activity and toxicity of the GAT (gemcitabine, doxorubicin and paclitaxel) regimen, derived from experimental preclinical studies, as first-line chemotherapy in patients with stage IIIB-IV breast cancer. METHODS: Patients with locally advanced or metastatic breast cancer and at least one bidimensionally measurable lesion were included in the present study. Adequate bone marrow reserve, normal cardiac, hepatic and renal function, and an ECOG performance status of 0 to 2 were required. Only prior adjuvant non anthracycline-based chemotherapy was permitted. Treatment consisted of doxorubicin 50 mg/m(2 )on day 1, paclitaxel 160 mg/m(2 )on day 2 and gemcitabine 800 mg/m(2 )on day 6, repeated every 21–28 days. RESULTS: Thirty-three consecutive breast cancer patients were enrolled onto the trial (7 stage IIIB and 26 stage IV). All patients were evaluable for toxicity and 29 were assessable for response. A total of 169 cycles were administered, with a median of 6 cycles per patient (range 1–8 cycles). Complete and partial responses were observed in 6.9% and 48.3% of patients, respectively, for an overall response rate of 55.2%. A response was reported in all metastatic sites, with a median duration of 16.4 months. Median time to progression and overall survival were 10.2 and 36.4 months, respectively. The most important toxicity was hematological, with grade III-IV neutropenia observed in 69% of patients, sometimes requiring the use of granulocyte colony-stimulating factor (27%). Non hematological toxicity was rare and mild. One patient died from sepsis during the first treatment cycle before the administration of gemcitabine. CONCLUSION: The strong synergism among the three drugs found in the preclinical setting was confirmed in terms of both clinical activity and hematological toxicity. Our results seem to indicate that the GAT regimen is effective in anthracycline-naïve metastatic breast cancer and provides a feasible chemotherapeutic option in this clinical setting

Activity of endovesical gemcitabine in BCG-refractory bladder cancer patients: a translational study

Intravesical gemcitabine (Gem) has shown promising activity against transitional cell carcinomas (TCC) of the bladder, with moderate urinary toxicity and low systemic absorption. The present phase II study evaluated the activity of biweekly intravesical treatment with Gem using a scheme directly derived from in vitro preclinical studies. Patients with Bacille Calmette-Guérin (BCG) -refractory Ta G3, T1 G1-3 TCC underwent transurethral bladder resection and then intravesical instillation with 2000 mg Gem diluted in 50 ml saline solution on days 1 and 3 for 6 consecutive weeks. Thirty-eight (95%) of the 40 patients showed persistent negative post-treatment cystoscopy and cytology 6 months after Gem treatment, while the remaining 2 patients relapsed at 5 and 6 months. At a median follow-up of 28 months, recurrences had occurred in 14 patients. Among these, four had downstaged (T) disease, three had a lower grade (G) lesion and three had a reduction in both T and G. Urinary and systemic toxicity was very low, with no alterations in biochemical profiles. In conclusion, biweekly instillation of Gem proved active in BCG-refractory Ta G3, T1 G1-3 TCC. Our results highlight the importance of preclinical studies using in vitro systems that adequately reproduce the conditions of intravesical clinical treatment to define the best therapeutic schedule

In vitro irradiation system for radiobiological experiments

Background: Although two-dimensional (2-D) monolayer cell cultures provide important information on basic tumor biology and radiobiology, they are not representative of the complexity of three-dimensional (3-D) solid tumors. In particular, new models reproducing clinical conditions as closely as possible are needed for radiobiological studies to provide information that can be translated from bench to bedside. Methods: We developed a novel system for the irradiation, under sterile conditions, of 3-D tumor spheroids, the in vitro model considered as a bridge between the complex architectural organization of in vivo tumors and the very simple one of in vitro monolayer cell cultures. The system exploits the same equipment as that used for patient treatments, without the need for dedicated and highly expensive instruments. To mimic the passage of radiation beams through human tissues before they reach the target tumor mass, 96-multiwell plates containing the multicellular tumor spheroids (MCTS) are inserted into a custom-built phantom made of plexiglass, the material most similar to water, the main component of human tissue. Results: The system was used to irradiate CAEP- and A549-derived MCTS, pre-treated or not with 20 \u3bcM cisplatin, with a dose of 20 Gy delivered in one session. We also tested the same treatment schemes on monolayer CAEP and A549 cells. Our preliminary results indicated a significant increment in radiotoxicity 20 days after the end of irradiation in the CAEP spheroids pre-treated with cisplatin compared to those treated with cisplatin or irradiation alone. Conversely, the effect of the radio- chemotherapy combination in A549-derived MCTS was similar to that induced by cisplatin or irradiation alone. Finally, the 20 Gy dose did not affect cell survival in monolayer CAEP and A549 cells, whereas cisplatin or cisplatin plus radiation caused 100% cell death, regardless of the type of cell line used. Conclusions: We set up a system for the irradiation, under sterile conditions, of tumor cells grown in 3-D which allows for the use of the same dose intensities and schedules utilized in clinical practice. This irradiation system, coupled with 3-D cell cultures, has the potential to generate information that could be used to individually tailor radiotherap

Addition of 5-fluorouracil to doxorubicin-paclitaxel sequence increases caspase-dependent apoptosis in breast cancer cell lines

INTRODUCTION: The aim of the study was to evaluate the activity of a combination of doxorubicin (Dox), paclitaxel (Pacl) and 5-fluorouracil (5-FU), to define the most effective schedule, and to investigate the mechanisms of action in human breast cancer cells. METHODS: The study was performed on MCF-7 and BRC-230 cell lines. The cytotoxic activity was evaluated by sulphorhodamine B assay and the type of drug interaction was assessed by the median effect principle. Cell cycle perturbation and apoptosis were evaluated by flow cytometry, and apoptosis-related marker (p53, bcl-2, bax, p21), caspase and thymidylate synthase (TS) expression were assessed by western blot. RESULTS: 5-FU, used as a single agent, exerted a low cytotoxic activity in both cell lines. The Dox→Pacl sequence produced a synergistic cytocidal effect and enhanced the efficacy of subsequent exposure to 5-FU in both cell lines. Specifically, the Dox→Pacl sequence blocked cells in the G2-M phase, and the addition of 5-FU forced the cells to progress through the cell cycle or killed them. Furthermore, Dox→Pacl pretreatment produced a significant reduction in basal TS expression in both cell lines, probably favoring the increase in 5-FU activity. The sequence Dox→Pacl→48-h washout→5-FU produced a synergistic and highly schedule-dependent interaction (combination index < 1), resulting in an induction of apoptosis in both experimental models regardless of hormonal, p53, bcl-2 or bax status. Apoptosis in MCF-7 cells was induced through caspase-9 activation and anti-apoptosis-inducing factor hyperexpression. In the BRC-230 cell line, the apoptotic process was triggered only by a caspase-dependent mechanism. In particular, at the end of the three-drug treatment, caspase-8 activation triggered downstream executioner caspase-3 and, to a lesser degree, caspase-7. CONCLUSION: In our experimental models, characterized by different biomolecular profiles representing the different biology of human breast cancers, the schedule Dox→Pacl→48-h washout→5-FU was highly active and schedule-dependent and has recently been used to plan a phase I/II clinical protocol

Neuron-glia cross talk in rat striatum after transient forebrain ischemia

Striatum is highly vulnerable to transient forebrain ischemia induced by the 4 vessel occlusion (4V0) method (Brierley 1976. Pulsinelli et al. 1982, Zini et al. 1990a). Massive degeneration and loss of Nissl-stained neurons occur within 24 hr from an ischemia of long duration (30 min) (Pulsinelli et al. 1982). Neuronal loss is mainly restricted to the lateral part of caudate-putamen (Pulsinelli et al. 1982, Zini et al. 1990a). Cellular alterations include loss of medium-size spiny projection neurons (Pulsinelli et al. 1982, Francis and Pulsinelli 1982), largely corresponding to dopaminoceptive neurons (Benfenati et al. 1989, Zoli et al. 1989), and increase in reactive astrocytes (Pulsinelli et al. 1982, Grimaldi et al. 1990) and microglia (Gehrmann et al. 1982). On the other hand, large cholinergie (Francis and Pulsinelli 1982) and medium-size aspiny somatostatin (SS)/neuropeptide Y (NPY)-containing interneurons are resistant to the ischemic insult (Pulsinelli et al. 1982, Grimaldi et al. 1990). In a few instances, such as in the case of SS and NPY immunoreactivity (IR), the initial loss is followed by full recovery within 7 (SS) or 40 (NPY) days post-ischemia (Grimaldi et al. 1990). However, it is not known whether some kind of recovery is present for the bulk of medium-size spiny projections neurons after the first days post-ischemia