Pt(IV)Ac-POA: new platinum compound Induced caspase independent apoptosis In B50 neuroblastoma stem cells

Neuroblastoma is a tumour that affects adults and children, characterized by a stem cells component. To date, cisplatin is the main antitumor agent used in the clinical treatment of this tumour; however, it induces side effects such as neurotoxicity in healthy cells and induces chemo resistance to therapy in cancer cells. New platinum-based compounds, platinum (II) have recently been synthesized, and due to their chemical characteristics, they are able to identify new cellular targets. These complexes act as prodrugs and performing their cytotoxic effect as platinum (II) after a reduction reaction within the hypoxic tumour cells. Among these prodrugs, Pt(IV)Ac-POA appears to be very promising, thanks to the presence of ligand (2 propinyl)octanoic acid (POA), which acts as an inhibitor of histone deacetylase (HDACi) and leads to the increase of histone acetylation, decreasing the interactions between histone and DNA, so as to produce chemo-sensitization to DNA-damaging agents. The greater cytotoxic effect of Pt(IV)Ac-POA on tumour cells, would therefore be mainly due to the mechanism of inhibition of histone deacetylase, which would increase the accessibility of DNA to platination mechanisms that induce cell death. In this study the results show that Pt(IV)Ac-POA, used at a concentration ten times lower than cisplatin, can induce apoptosis in B50 cells in culture both through the intrinsic pathway and through the independent caspase pathway. The data, obtained by immunohistochemical techniques in fluorescence microscopy, show that treatment with Pt(IV)Ac-POA has a greater proapoptotic effect on stem cells compared to the cisplatin standard treatment

Substantiation of buried two dimensional hole gas (2DHG) existence in GaN-on-Si epitaxial heterostructure

Gallium Nitride on Silicon (GaN-on-Si) devices feature a relatively thick epi buffer layer to release the stress related to the lattice constant mismatch between GaN and Si. The buffer layer is formed by several AlGaN-based transition layers with different Al contents. This work addresses the fundamental question of whether two-dimensional hole gases (2DHGs) exist at those interfaces where the theory predicts a high concentration of a negative fixed charge as a consequence of the discontinuity in polarization between the layers. In this study, we demonstrate that the presence of such 2DHGs is consistent with the measured vertical Capacitance-Votage Profiling (CV) and Technology Caomputer-Aided Design (TCAD) simulation in the whole range of measurable frequencies (10 mHz–1 MHz). N-type compensating background donor included in the epi structure in the simulation deck proves to be crucial to explain the depletion region extension consistent with the CV experimental data. For the standard range of frequencies (1 kHz–1 MHz), there was no indication of the presence of 2DHGs. A set of ultra-low frequency (10 mHz–10 Hz) measurements performed were able to reveal the existence of 2DHGs. The outcome of these ultra-low frequency experiments was matched with TCAD simulations which validated our theory

On the vertical leakage of GaN-on-Si lateral transistors and the effect of emission and trap-to-trap-tunneling through the AlN/Si barrier

Vertical leakage in lateral GaN devices has a significant contribution to the overall off-state current at high blocking voltages and high temperatures. It could could lead to premature breakdown before avalanche or dielectric breakdown occur. This paper identifies via experimental results and TCAD simulations the main physical mechanisms responsible for the vertical leakage through the epi and transition layer structure: (i) silicon impact ionization, (ii) electron injection across the AlN nucleation layer/silicon interface, (iii) space charge limited current. In particular, the trap-to-trap model, accounting for the leakage current across the nucleation layer, was implemented showing to be dominant at lower voltages (<200V)

JNK signaling activation in the Ube3a maternal deficient mouse model: Its specific inhibition prevents post-synaptic protein-enriched fraction alterations and cognitive deficits in Angelman Syndrome model

Deficiency of the E3 ubiquitin ligase UBE3A leads to the neurodevelopmental disorder Angelman syndrome (AS), while higher levels are linked to autism spectrum disorder. The mechanisms underlying the downstream effects of UBE3A loss or gain of function in these disorders are still not well understood, and treatments are still lacking. Here, using the Ube3a maternal loss (Ube3am-/p+) mouse model, we report an important JNK signaling activation in the hippocampus, cortex and cerebellum correlating with the onset of behavioral defects and biochemical marker alterations in the post-synaptic element, suggesting important spine pathology. JNK activation occurs at 7 and persists up till 23\u202fweeks in Ube3am-/p+ mice in two different cellular compartments: the nucleus and the post-synaptic protein-enriched fraction. To study JNK's role in Ube3am-/p+ pathology we treated mice with the specific JNK inhibitor peptide, D-JNKI1, from 7 to 23\u202fweeks of age. Preventing JNK action in vivo restores the post-synaptic protein-enriched fraction defects and the cognitive impairment in these mice. Our results imply a critical role of UBE3A-JNK signaling in the pathogenesis of UBE3A-related disorders. In particular, it was clear that JNK is a key player in regulating AS synaptic alterations and the correlated cognitive impairments, in fact, its specific inhibition tackles Ube3am-/p+ pathology. This study sheds new light on the neuronal functions of UBE3A and offers new prospects for understanding the pathogenesis of UBE3A-related disorders

On the vertical leakage of GaN-on-Si lateral transistors and the effect of emission and trap-to-trap-tunneling through the AlN/Si barrier

Vertical leakage in lateral GaN devices has a significant contribution to the overall off-state current at high blocking voltages and high temperatures. It could could lead to premature breakdown before avalanche or dielectric breakdown occur. This paper identifies via experimental results and TCAD simulations the main physical mechanisms responsible for the vertical leakage through the epi and transition layer structure: (i) silicon impact ionization, (ii) electron injection across the AlN nucleation layer/silicon interface, (iii) space charge limited current. In particular, the trap-to-trap model, accounting for the leakage current across the nucleation layer, was implemented showing to be dominant at lower voltages (<200V).Infineon Technologies Corp US

Pt(Iv)Ac-POA: New Platinum Compound Induced Caspase Independent Apoptosis In B50 Neuroblastoma Stem Cells

Neuroblastoma is a tumour that affects adults and children, characterized by a stem cells component. To date, cisplatin is the main antitumor agent used in the clinical treatment of this tumour; however, it induces side effects such as neurotoxicity in healthy cells and induces chemo resistance to therapy in cancer cells. New platinum-based compounds, platinum (II) have recently been synthesized, and due to their chemical characteristics, they are able to identify new cellular targets. These complexes act as prodrugs and performing their cytotoxic effect as platinum (II) after a reduction reaction within the hypoxic tumour cells. Among these prodrugs, Pt(IV)Ac-POA appears to be very promising, thanks to the presence of ligand (2 propinyl)octanoic acid (POA), which acts as an inhibitor of histone deacetylase (HDACi) and leads to the increase of histone acetylation, decreasing the interactions between histone and DNA, so as to produce chemo-sensitization to DNA-damaging agents. The greater cytotoxic effect of Pt(IV)Ac-POA on tumour cells, would therefore be mainly due to the mechanism of inhibition of histone deacetylase, which would increase the accessibility of DNA to platination mechanisms that induce cell death. In this study the results show that Pt(IV)Ac-POA, used at a concentration ten times lower than cisplatin, can induce apoptosis in B50 cells in culture both through the intrinsic pathway and through the independent caspase pathway. The data, obtained by immunohistochemical techniques in fluorescence microscopy, show that treatment with Pt(IV)Ac-POA has a greater proapoptotic effect on stem cells compared to the cisplatin standard treatment

Effect of Bandgap Narrowing on Performance of Modern Power Devices

The effect of the bandgap narrowing (BGN) on performance of power devices has been investigated in detail in this paper. The analysis has revealed that the change in the energy band structure caused by bandgap narrowing can strongly affect the conductivity modulation of the bipolar devices resulting in completely different performance. This is due to the modified injection efficiency under high level injection conditions. Using a comprehensive analysis of the injection efficiency in a p-n junction an analytical model for this phenomenon has been developed. Bandgap narrowing model tuning has been proved to be essential in accurately predicting the performance of a Lateral IGBT. Other devices such as PIN diodes or PT IGBTs are significantly affected by the BGN while others, such as FS IGBT or the power MOSFET, are only marginally affected

New platinum-based prodrug Pt(IV)Ac-POA: antitumour effects in Rat C6 Glioblastoma cells

Gliomas are the most frequent primary tumours of the nervous system, characterised by high degree of malignancy, widespread invasion and high-rate proliferation. Cisplatin and analogue are currently employed in clinical trials as active chemotherapeutic agents for the systemic treatment of this type of malignancy. Despite therapy benefits, clinical use of these agents is hampered by severe side effects including neurotoxicity. Therefore, the aim of the present study was to analyse the effect of a new compound of platinum(IV) conjugate, named Pt(IV)Ac-POA, which can generate a synergistic antineoplastic action when released along with cisplatin, after a specific reduction reaction within tumour cells. To assess the effects of the novel compound on rat C6 glioma cells, cell cycle and cell death activation analyses were carried out using flow cytometry. Morphological changes and activation of different cell death pathways were evaluated by both transmission electron microscopy and immunofluorescence microscopy. Protein expression was investigated by western blotting analysis. The novel compound Pt(IV)Ac-POA, bearing as axial ligand (2-propynyl)octanoic acid (POA), which is a histone deacetylase inhibitor (HDACi), acts as a prodrug in tumour cells, inducing cell death through different pathways at a concentration lower than those tested for other platinum analogues. The current results showed that Pt(IV)Ac-POA could represent a promising improvement of Pt-based chemotherapy against gliomas, either inducing a chemosensitisation and reducing chemoresistance

Independent Contributions of Nocturnal Hot Flashes and Sleep Disturbance to Depression in Estrogen-Deprived Women

CONTEXT: Women are at increased risk for mood disturbance during the menopause transition. Hot flashes (HFs), sleep disruption, and fluctuating estradiol levels correlate with menopause-associated depression but co-occur, making cause and effect relationships difficult to disentangle. OBJECTIVE: Using a GnRH agonist (GnRHa) experimental model, we investigated whether depressive symptoms are associated with HFs and/or are explained by concomitant sleep fragmentation in the absence of estradiol fluctuation. DESIGN AND INTERVENTION: Depressive symptoms, objective polysomnographic sleep parameters, subjective sleep quality, serum estradiol, and HFs were assessed before and 4 weeks after open-label depot GnRHa (leuprolide 3.75-mg) administration. SETTING: Academic medical center. PARTICIPANTS: Twenty-nine healthy nondepressed premenopausal volunteers (mean age, 27.3 years). RESULTS: Serum estradiol was rapidly and uniformly suppressed. HFs developed in 69% of the subjects. On univariate analysis, worsening of mood was predicted by increases in time in light sleep (stage N1), number of transitions to wake, non-REM arousals, subjective sleep quality, and reductions in perceived sleep efficiency (all P \u3c .045), as well as the number of nighttime (P = .006), but not daytime (P = .28), HFs reported. In adjusted models, the number of nighttime HFs reported, increases in non-REM arousals, time in stage N1, transitions to wake, and reduced sleep quality remained significant predictors of mood deterioration (P CONCLUSIONS: Depressive symptoms emerged after estradiol withdrawal in association with objectively and subjectively measured sleep disturbance and the number of nighttime, but not daytime, HFs reported. Results suggest that sleep disruption and perceived nighttime HFs both contribute to vulnerability to menopause-associated depressive symptoms in hypoestrogenic women