Tunable spin polarization and superconductivity in engineered oxide interfaces.

Advances in growth technology of oxide materials allow single atomic layer control of heterostructures. In particular delta doping, a key materials' engineering tool in today's semiconductor technology, is now also available for oxides. Here we show that a fully electric-field-tunable spin-polarized and superconducting quasi-2D electron system (q2DES) can be artificially created by inserting a few unit cells of delta doping EuTiO3 at the interface between LaAlO3 and SrTiO3 oxides. Spin polarization emerges below the ferromagnetic transition temperature of the EuTiO3 layer (TFM = 6-8 K) and is due to the exchange interaction between the magnetic moments of Eu-4f and of Ti-3d electrons. Moreover, in a large region of the phase diagram, superconductivity sets in from a ferromagnetic normal state. The occurrence of magnetic interactions, superconductivity and spin-orbit coupling in the same q2DES makes the LaAlO3/EuTiO3/SrTiO3 system an intriguing platform for the emergence of novel quantum phases in low-dimensional materials.

SNORD116 deletions cause Prader-Willi syndrome with a mild phenotype and macrocephaly.

Prader-Willi syndrome is a complex condition caused by lack of expression of imprinted genes in the paternally derived region of chromosome 15 (15q11q13). A small number of patients with Prader-Willi phenotype have been discovered to have narrow deletions, not encompassing the whole critical region, but only the SNORD116 cluster, which includes genes codifying for small nucleolar RNAs. This kind of deletion usually is not detected by the classic DNA methylation analysis test. We present the case of a male patient with a mild Prader-Willi phenotype and a small deletion including SNORD116, diagnosed by methylation-sensitive multiplex ligation-dependent probe amplification (MLPA. The patient showed neonatal hypotonia, hyperphagia, obesity, central hypogonadism, hypothyroidism, strabismus. Stature and intellectual development are within the normal range. The presence of macrocephaly, observed in other cases of SNORD116 deletions as well, is uncommon for the classic phenotype of the syndrome.

Regorafenib monotherapy as second-line treatment of patients with RAS-mutant advanced colorectal cancer (STREAM): an academic, multicenter, single-arm, two-stage, phase II study.

BACKGROUND: Maintaining angiogenesis inhibition and switching the chemotherapy backbone represent the current second-line therapy in patients with RAS-mutant metastatic colorectal cancer (mCRC). Regorafenib, an oral multikinase inhibitor, prolonged overall survival (OS) in the chemorefractory setting. MATERIALS AND METHODS: STREAM was an academic, multicenter, single-arm phase II trial, evaluating the activity of regorafenib in RAS-mutant mCRC, in terms of the rate of patients who were progression-free after 6 months from study entry (6mo-PF). Patients were pretreated with fluoropyrimidine, oxaliplatin, and bevacizumab. According to Simon's two-stage design, ≥18 patients 6mo-PF were needed in the overall population (N = 46). Secondary endpoints were safety, objective response rate (ORR), progression-free survival (PFS), and OS. Early metabolic response by [18F]2-fluoro-2-deoxy-D-glucose-positron emission tomography/computed tomography ([18F]-FDG PET/CT) scan was an exploratory endpoint. EudraCT Number: 2015-001105-13. RESULTS: The number of patients 6mo-PF was 8/22 at the first stage and 14/46 in the overall population. The ORR was 10.9%, disease control rate was 54.6%, median (m)PFS was 3.6 months [95% confidence interval (CI) 1.9-6.7 months], mOS was 18.9 months (95% CI 10.3-35.3 months), and mPFS2 (from study entry to subsequent-line progression) was 13.3 months (95% CI 8.4-19.7 months). Long benefiter patients (>6mo-PF) significantly more often had a single metastatic site and lung-limited disease. No unexpected toxicity was reported. Grade ≥3 events occurred in 39.1% of patients, with hand-foot syndrome (13%), fatigue, and hyperbilirubinemia (6.5%) occurring mostly. Baseline metabolic assessment was associated with OS in the multivariate analysis, while early metabolic response was not associated with clinical outcomes. CONCLUSIONS: The study did not meet its primary endpoint. However, regorafenib was well tolerated and did not preclude subsequent treatments. Patients with good prognostic features (single metastatic site and lung-limited disease) reported clinical benefit with regorafenib. The exploratory metabolic analysis suggests that baseline [18F]-FDG PET/CT might be useful to select patients with a favorable outcome. A chemotherapy-free interval with regorafenib was associated with durable disease control in a selected group of patients with favorable clinical characteristics.

Vorinostat synergises with capecitabine through upregulation of thymidine phosphorylase.

BACKGROUND: Potentiation of anticancer activity of capecitabine is required to improve its therapeutic index. In colorectal cancer (CRC) cells, we evaluated whether the histone deacetylase-inhibitor vorinostat may induce synergistic antitumour effects in combination with capecitabine by modulating the expression of thymidine phosphorylase (TP), a key enzyme in the conversion of capecitabine to 5-florouracil (5-FU), and thymidylate synthase (TS), the target of 5-FU. METHODS: Expression of TP and TS was measured by real-time PCR, western blotting and immunohistochemistry. Knockdown of TP was performed by specific small interfering RNA. Antitumour activity of vorinostat was assessed in vitro in combination with the capecitabine active metabolite deoxy-5-fluorouridine (5'-DFUR) according to the Chou and Talay method and by evaluating apoptosis as well as in xenografts-bearing nude mice in combination with capecitabine. RESULTS: Vorinostat induced both in vitro and in vivo upregulation of TP as well as downregulation of TS in cancer cells, but not in ex vivo treated peripheral blood lymphocytes. Combined treatment with vorinostat and 5'-DFUR resulted in a synergistic antiproliferative effect and increased apoptotic cell death in vitro. This latter effect was impaired in cells where TP was knocked. In vivo, vorinostat plus capecitabine potently inhibited tumour growth, increased apoptosis and prolonged survival compared with control or single-agent treatments. CONCLUSIONS: Overall, this study suggests that the combination of vorinostat and capecitabine is an innovative antitumour strategy and warrants further clinical evaluation for the treatment of CRC.

Transition from a uni- to a bimodal interfacial charge distribution in [Formula: see text]/[Formula: see text] upon cooling.

We present a combined resonant soft X-ray reflectivity and electric transport study of [Formula: see text]/[Formula: see text] field effect devices. The depth profiles with atomic layer resolution that are obtained from the resonant reflectivity reveal a pronounced temperature dependence of the two-dimensional electron liquid at the [Formula: see text]/[Formula: see text] interface. At room temperature the corresponding electrons are located close to the interface, extending down to 4 unit cells into the [Formula: see text] substrate. Upon cooling, however, these interface electrons assume a bimodal depth distribution: They spread out deeper into the [Formula: see text] and split into two distinct parts, namely one close to the interface with a thickness of about 4 unit cells and another centered around 9 unit cells from the interface. The results are consistent with theoretical predictions based on oxygen vacancies at the surface of the [Formula: see text] film and support the notion of a complex interplay between structural and electronic degrees of freedom.

Pendellösung effect in photonic crystals.

At the exit surface of a photonic crystal, the intensity of the diffracted wave can be periodically modulated, showing a maximum in the "positive" (forward diffracted) or in the "negative" (diffracted) direction, depending on the slab thickness. This thickness dependence is a direct result of the so-called Pendell osung phenomenon, consisting of the periodic exchange inside the crystal of the energy between direct and diffracted beams. We report the experimental observation of this effect in the microwave region at about 14GHz by irradiating 2D photonic crystal slabs of different thickness and detecting the intensity distribution of the electromagnetic field at the exit surface and inside the crystal itself.

EGF activates an inducible survival response via the RAS-> Erk-1/2 pathway to counteract interferon-alpha-mediated apoptosis in epidermoid cancer cells.

The mechanisms of tumor cell resistance to interferon-alpha (IFNalpha) are at present mostly unsolved. We have previously demonstrated that IFNalpha induces apoptosis on epidermoid cancer cells and EGF antagonizes this effect. We have also found that IFNalpha-induced apoptosis depends upon activation of the NH(2)-terminal Jun kinase-1 (Jnk-1) and p(38) mitogen-activated protein kinase, and that these effects are also antagonized by EGF. At the same time, IFNalpha increases the expression and function of the epidermal growth factor receptor (EGF-R). Here we report that the apoptosis induced by IFNalpha occurs together with activation of caspases 3, 6 and 8 and that EGF also antagonizes this effect. On the basis of these results, we have hypothesized that the increased EGF-R expression and function could represent an inducible survival response that might protect tumor cells from apoptosis caused by IFNalpha via extracellular signal regulated kinase 1 and 2 (Erk-1/2) cascades. We have found an increased activity of Ras and Raf-1 in IFNalpha-treated cells. Moreover, IFNalpha induces a 50% increase of the phosphorylated isoforms and enzymatic activity of Erk-1/2. We have also demonstrated that the inhibition of Ras activity induced by the transfection of the dominant negative Ras plasmid RASN17 and the inhibition of Mek-1 with PD098059 strongly potentiates the apoptosis induced by IFNalpha. Moreover, the selective inhibition of this pathway abrogates the counteracting effect of EGF on the IFNalpha-induced apoptosis. All these findings suggest that epidermoid tumor cells counteract the IFNalpha-induced apoptosis through a survival pathway that involves the hyperactivation of the EGF-dependent Ras->Erk signalling. The selective targeting of this pathway appears to be a promising approach in order to enhance the antitumor activity of IFNalpha.

Docetaxel induces p53-dependent apoptosis and synergizes with farnesyl transferase inhibitor r115777 in human epithelial cancer cells.

Docetaxel (Taxotere, DTX) is a promoter of apoptosis in cancer cells. Since cytotoxic mechanisms of DTX are not yet fully understood, we have investigated the effects of DTX on apoptosis and ras-->Erk-mediated signal transduction in human epidermoid KB, colon HT-29 and breast HCC1937 cancer cells. We have found that the exposure to 0.78 or 1.56 or 2.5 ng/ml DTX for 48 h induced apoptosis and growth inhibition in about 50 % of KB, HCC1937 and HT-29 cell population, respectively. In these experimental conditions, PARP and caspase 3 cleavage was also showed in all cell lines. KB and HCC1937 cells express a wild type p53 while HT-29 display a mutated form. Interestingly, we have found that DTX reduces the expression of mutated p53 in HT-29 and increases the expression of wild type in KB and HCC1937 cells. Moreover, DTX reduces ubiquitination of the wild type p53 in KB and HCC1937 cells and increases the ubiquitin-conjugated form of mutated p53 in HT-29 cells. Furthermore, exposure of cancer cells to DTX for 48 h increases the expression and activity of Ras and up-regulates Raf-1 and the phosphorylated isoforms of Erk-1/2. On the bases of these data, we have hypothesized that the increased activity of the ras-->erk-dependent pathway induced by DTX could be a protective signalling from the apoptosis caused by the drug. Therefore, we have used R115777, a farnesyl transferase inhibitor that inactivates ras, in combination with DTX. The combined treatment with DTX and R115777 resulted in a strong synergism in growth inhibition in the three cell lines. These data suggest the use of the combination in these therapeutic settings even if further experiments are required for the clinical translation.

Multiple-target drugs: inhibitors of heat shock protein 90 and of histone deacetylase.

In spite of the improvement of conventional medical therapy for cancer treatment, the impact on cancer related mortality in the last ten years has been modest especially for advanced disease in adults. On the other hand, understanding of molecular events underlining tumor development lead to the definition of new molecular targets for novel anti-tumor therapeutical approaches. On this regard, several biotechnology products selected by academic as well as industrial research are currently in clinical trials. Epigenetics as well as post-translational modifications of proteins are emerging as novel attractive targets for anticancer therapy. In addition, the heterogeneity of tumor cells within a selected neoplastic lesions as well as the redundancy of proliferative and survival pathways present in cancer cells favor the development of single drugs that are able to affect multiple pathways. Inhibitors of heat shock protein 90 and of histone deacetylase are two novel classes of multi-target agents that entered recently in clinical studies. This review will focus on the most important issues in the development of both these classes of agents.

Up-regulated EGF receptors undergo to rapid internalization and ubiquitin-dependent degradation in human cancer cells exposed to 8-Cl-cAMP.

8-Cl-cAMP, a cAMP analogue that antagonizes type I cAMP-dependent protein kinase, is a novel anti-tumor agent presently under investigation in clinical trials. Herein we report the effects of this agent on epidermal growth factor receptor expression and degradation in human KB cancer cells. Exposure to 10 microM 8-Cl-cAMP for 48 h induced a 65% increase in epidermal growth factor receptor surface expression while the receptor synthesis was 22-fold enhanced. Analysis of epidermal growth factor-dependent receptor internalization in 8-Cl-cAMP-treated cells showed a higher endocytosis rate as well as an accelerated degradation which occurred together with an increased receptor ubiquitination. The enhanced degradation of epidermal growth factor receptor correlated with the lack of epidermal growth factor-induced proliferation and mitogen-activated protein kinase stimulation. The disregulation of epidermal growth factor receptor internalization and ubiquitin-dependent degradation could underlay a new mechanism of the anti-tumor activity of 8-Cl-cAMP suggesting its combination with agents that disrupt epidermal growth factor receptor signalling.

Absence of mutations in major GEFS+ genes in myoclonic astatic epilepsy.

Myoclonic astatic epilepsy (MAE) is a genetically determined condition of childhood onset characterized by multiple generalized types of seizures including myoclonic astatic seizures, generalized spike waves and cognitive deterioration. This condition has been reported in a few patients in generalized epilepsy with febrile seizures plus (GEFS+) families and MAE has been considered, like severe myoclonic epilepsy of infancy (SMEI), to be a severe phenotype within the GEFS+ spectrum. Four genes have been identified in GEFS+ families, but only three (SCN1A, SCNlB, GABRG2) were found in MAE patients within GEFS+ families. We analysed these three genes in a series of 22 sporadic patients with MAE and found no causal mutations. These findings suggest that MAE, unlike SMEI, is not genetically related to GEFS+. Although MAE and SMEI share the same types of seizures, only SMEI patients are sensitive to fever. This is probably its main link to GEFS+. A different family of genes is likely to account for MAE.

No evidence for a susceptibility locus for idiopathic generalized epilepsy on chromosome 5 in families with typical absence seizures.

A recent genome-wide scan revealed suggestive evidence for two susceptibility loci for idiopathic generalized epilepsy (IGE) in the chromosomal regions 5p15 and 5q14-q22 in families with typical absence seizures. The present replication study tested the validity of the tentative IGE loci on chromosome 5. Our study included 99 multiplex families in which at least one family member had typical absence seizures. Parametric and non-parametric multipoint linkage analyses were carried out between the IGE trait and 23 microsatellite polymorphisms covering the entire region of chromosome 5. Multipoint parametric heterogeneity lod scores < -2 were obtained along chromosome 5 when a proportion of linked families greater than 50% was assumed under recessive inheritance and > 60% under dominant inheritance. Furthermore, non-parametric multipoint linkage analyses revealed no hint of linkage throughout the candidate region (P > 0.05). Accordingly, we failed to support previous evidence for common IGE loci on chromosome 5. If there is a susceptibility locus for IGE on chromosome 5 then the size of the effect or the proportion of linked families is too small to detect linkage in the investigated family sample.

Effect of aerobic training on the cognitive performance of elderly patients with senile dementia of Alzheimer type.

The importance of physical activity to maintain a healthy psychological functions is widely known. The present study involved 15 males affected by senile dementia of Alzheimer type (SDAT) and assessed their functional capabilities by means of the following neuropsychological tests: test of attentional matrix, verbal span test, supraverbal span test, mini mental state examination. After an exercise training program of 3 months, patients were assessed again by the same psychological tests which demonstrated a significant improvement.

A case report on the effect of training and low caloric diet in hypertension, obesity and hyperinsulinemia.

In an obese hypertensive woman affected by angina-like chest pain, a physical training program and a low caloric diet resulted in a notable improvement of the anthropometric indexes, hyperinsulinemia, myocardial perfusion and left ventricular mass.

Acute gonococcal urethritis: treatment with a single dose of rifampicin.

A total of 103 patients with acute gonococcal urethritis were treated with a single 1,200 mg dose of rifampicin. A 91 . 3% cure rate was obtained, as proved by the negative bacteriological controls effected on the 7th and 14th days after the initiation of therapy. Three pharyngeal infections and one ano-rectal infection responded successfully to the treatment. No signs of drug intolerance were detected with the stated dose. Reactivity to the VDRL test was not impaired during the duration of the study and three reactive cases were discovered. In previous studies of gonorrhoea we had observed a significant discrepancy between urine cultures and the urethral smears and, in view of this, it was decided to adopt the latter alone as a routine procedure. The proposed dose does not originate resistance to rifampicin in either the Hansen or Koch bacilli.

[Spontaneous splenic rupture due to infectious acute mononucleosis: case report]. / Rottura splenica spontanea in corso di mononuleosi infettiva acuta: descrizione di un caso.

Infectious mononucleosis is an acute, viral, illness associated with a high incidence of splenomegaly. Spontaneous splenic rupture is a rare but life-threatening complication of infectious mononucleosis. The authors report the case of a 19-year-old patient with an infectious mononucleosis causing a spontaneous splenic rupture. When rupture occurs the mortality has been significant. The spleen may be vulnerable for the histopathologic changes that occur as a result of this illness. Two thirds of patients with infectious mononucleosis develop an enlarged spleen, but in only 0.5% of all patients will it rupture. Abdominal pain and tachycardia are unusual in uncomplicated infectious mononucleosis and should alert a doctor to the possibility of spontaneous splenic rupture. The diagnosis of splenic rupture may be confirmed in a variety of ways. In this patient ultrasound and Rutkow's criteria may aid in establishing the diagnosis. In patients with infectious mononucleosis suspected of having rupture of the spleen, a rapid but thorough assessment and prompt implementation of appropriate management should minimize the associated morbidity and mortality. On the basis of review of the medical literature and of our own experience, we advocate emergent splenectomy for spontaneous splenic rupture in patients with infectious mononucleosis.

Acquired resistance to zoledronic acid and the parallel acquisition of an aggressive phenotype are mediated by p38-MAP kinase activation in prostate cancer cells.

The nitrogen-containing bisphosphonates (N-BP) zoledronic acid (ZOL) inhibits osteoclast-mediated bone resorption, and it is used to prevent skeletal complications from bone metastases. ZOL has also demonstrated anticancer activities in preclinical models and, recently, in cancer patients, highlighting the interest in determining eventual mechanisms of resistance against this agent. In our study, we selected and characterised a resistant subline of prostate cancer (PCa) cells to better understand the mechanisms, by which tumour cells can escape the antitumour effect of ZOL. DU145R80-resistant cells were selected in about 5 months using stepwise increasing concentrations of ZOL from DU145 parental cells. DU145R80 cells showed a resistance index value of 5.5 and cross-resistance to another N-BP, pamidronate, but not to the non-nitrogen containing BP clodronate. Notably, compared with DU145 parental cells, DU145R80 developed resistance to apoptosis and anoikis, as well as overexpressed the anti-apoptotic protein Bcl-2 and oncoprotein c-Myc. Moreover, DU145R80 cells underwent epithelial to mesenchymal transition (EMT) and showed increased expression of the metalloproteases MMP-2/9, as well as increased invading capability. Interestingly, compared with DU145, DU145R80 cells also increased the gene expression and protein secretion of VEGF and the cytokines Eotaxin-1 and IL-12. At the molecular level, DU145R80 cells showed strong activation of the p38-MAPK-dependent survival pathway compared with parental sensitive cells. Moreover, using the p38-inhibitor SB203580, we completely reversed the resistance to ZOL, as well as EMT marker expression and invasion. Furthermore, SB203580 treatment reduced the expression of VEGF, Eotaxin-1, IL-12, MMP-9, Bcl-2 and c-Myc. Thus, for the first time, we demonstrate that the p38-MAPK pathway can be activated under continuous extensive exposure to ZOL in PCa cells and that the p38-MAPK pathway has a critical role in the induction of resistance, as well as in the acquisition of a more aggressive and invasive phenotype.

Panobinostat synergizes with zoledronic acid in prostate cancer and multiple myeloma models by increasing ROS and modulating mevalonate and p38-MAPK pathways.

Patients with advanced prostate cancer (PCa) and multiple myeloma (MM) have limited long-term responses to available therapies. The histone deacetylase inhibitor panobinostat has shown significant preclinical and clinical anticancer activity in both hematological and solid malignancies and is currently in phase III trials for relapsed MM. Bisphosphonates (BPs), such as zoledronic acid (ZOL), inhibit osteoclast-mediated bone resorption and are indicated for the treatment of bone metastasis. BPs, including ZOL, have also shown anticancer activity in several preclinical and clinical studies. In the present report, we found a potent synergistic antiproliferative effect of panobinostat/ZOL treatment in three PCa and three MM cell lines as well as in a PCa ZOL-resistant subline, independently of p53/KRAS status, androgen dependency, or the schedule of administration. The synergistic effect was also observed in an anchorage-independent agar assay in both ZOL-sensitive and ZOL-resistant cells and was confirmed in vivo in a PCa xenograft model. The co-administration of the antioxidant N-acetyl-L-cysteine blocked the increased reactive oxygen species generation and apoptosis observed in the combination setting compared with control or single-agent treatments, suggesting that oxidative injury plays a functional role in the synergism. Proapoptotic synergy was also partially antagonized by the addition of geranyl-geraniol, which bypasses the inhibition of farnesylpyrophosphate synthase by ZOL in the mevalonate pathway, supporting the involvement of this pathway in the synergy. Finally, at the molecular level, the inhibition of basal and ZOL-induced activation of p38-MAPK by panobinostat in sensitive and ZOL-resistant cells and in tumor xenografts could explain, at least in part, the observed synergism.

Reduction of maternal mortality with highly active antiretroviral therapy in a large cohort of HIV-infected pregnant women in Malawi and Mozambique.

BACKGROUND: HIV infection is a major contributor to maternal mortality in resource-limited settings. The Drug Resource Enhancement Against AIDS and Malnutrition Programme has been promoting HAART use during pregnancy and postpartum for Prevention-of-mother-to-child-HIV transmission (PMTCT) irrespective of maternal CD4 cell counts since 2002. METHODS: Records for all HIV+ pregnancies followed in Mozambique and Malawi from 6/2002 to 6/2010 were reviewed. The cohort was comprised by pregnancies where women were referred for PMTCT and started HAART during prenatal care (n = 8172, group 1) and pregnancies where women were referred on established HAART (n = 1978, group 2). RESULTS: 10,150 pregnancies were followed. Median (IQR) baseline values were age 26 years (IQR:23-30), CD4 count 392 cells/mm(3) (IQR:258-563), Viral Load log10 3.9 (IQR:3.2-4.4), BMI 23.4 (IQR:21.5-25.7), Hemoglobin 10.0 (IQR: 9.0-11.0). 101 maternal deaths (0.99%) occurred during pregnancy to 6 weeks postpartum: 87 (1.1%) in group 1 and 14 (0.7%) in group 2. Mortality was 1.3% in women with

A systematic review of the literature concerning the relationship between obesity and mortality in the elderly.

INTRODUCTION: Obesity is a risk factor for chronic diseases and premature mortality, but the extent of these associations among the elderly is under debate. The aim of this systematic literature review (SR) is to collate and critically assess the available information of the impact of obesity on mortality in the elderly. METHODS: In PubMed, there are three-hundred twelve papers on the relationship between obesity and mortality among older adults. These papers were analysed on the basis of their abstracts, and sixteen studies were considered suitable for the purpose of the study. It was possible to perform a pooled estimate for aggregated data in three different studies. CONCLUSION: The results of this SR document that an increased mortality in obese older adults. The limitation of BMI to index obesity and the noted protective action of a moderate increase in BMI on mortality are highlighted. Waist circumference is an indicator of central adiposity and potentially as good a risk factor for mortality as BMI in obese elderly adults.