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In this paper, we report a multiscale investigation of the compositional, morphological, structural, electrical, and optical emission properties of 2H-MoS 2 obtained by sulfurization at 800 °C of very thin MoO 3 films (with thickness ranging from ~2.8 nm to ~4.2 nm) on a SiO 2 /Si substrate. XPS analyses confirmed that the sulfurization was very effective in the reduction of the oxide to MoS 2, with only a small percentage of residual MoO 3 present in the final film. High-resolution TEM/STEM analyses revealed the formation of few (i.e., 2-3 layers) of MoS 2 nearly aligned with the SiO 2 surface in the case of the thinnest (~2.8 nm) MoO 3 film, whereas multilayers of MoS 2 partially standing up with respect to the substrate were observed for the ~4.2 nm one. Such different configurations indicate the prevalence of different mechanisms (i.e., vapour-solid surface reaction or S diffusion within the film) as a function of the thickness. The uniform thickness distribution of the few-layer and multilayer MoS 2 was confirmed by Raman mapping. Furthermore, the correlative plot of the characteristic A 1g -E 2g Raman modes revealed a compressive strain (ε ≈ -0.78 ± 0.18%) and the coexistence of n- and p-type doped areas in the few-layer MoS 2 on SiO 2 , where the p-type doping is probably due to the presence of residual MoO 3 . Nanoscale resolution current mapping by C-AFM showed local inhomogeneities in the conductivity of the few-layer MoS 2 , which are well correlated to the lateral changes in the strain detected by Raman. Finally, characteristic spectroscopic signatures of the defects/disorder in MoS 2 films produced by sulfurization were identified by a comparative analysis of Raman and photoluminescence (PL) spectra with CVD grown MoS 2 flakes.

Objective: Cancer stem cells are responsible for tumour spreading and relapse. Human epidermal growth factor receptor 2 (HER2) expression is a negative prognostic factor in colorectal cancer (CRC) and a potential target in tumours carrying the gene amplification. Our aim was to define the expression of HER2 in colorectal cancer stem cells (CR-CSCs) and its possible role as therapeutic target in CRC resistant to anti- epidermal growth factor receptor (EGFR) therapy., Design: A collection of primary sphere cell cultures obtained from 60 CRC specimens was used to generate CR-CSC mouse avatars to preclinically validate therapeutic options. We also made use of the ChIP-seq analysis for transcriptional evaluation of HER2 activation and global RNA-seq to identify the mechanisms underlying therapy resistance., Results: Here we show that in CD44v6-positive CR-CSCs, high HER2 expression levels are associated with an activation of the phosphatidylinositol 3-kinase (PI3K)/AKT pathway, which promotes the acetylation at the regulatory elements of the Erbb2 gene. HER2 targeting in combination with phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase kinase (MEK) inhibitors induces CR-CSC death and regression of tumour xenografts, including those carrying Kras and Pik3ca mutation. Requirement for the triple targeting is due to the presence of cancer-associated fibroblasts, which release cytokines able to confer CR-CSC resistance to PI3K/AKT inhibitors. In contrast, targeting of PI3K/AKT as monotherapy is sufficient to kill liver-disseminating CR-CSCs in a model of adjuvant therapy., Conclusions: While PI3K targeting kills liver-colonising CR-CSCs, the concomitant inhibition of PI3K, HER2 and MEK is required to induce regression of tumours resistant to anti-EGFR therapies. These data may provide a rationale for designing clinical trials in the adjuvant and metastatic setting., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

4H-SiC based p-n junction UV photo-detectors were irradiated with 600 keV He + in the fluence range of 5 × 10 11 ÷ 5 × 10 14 ion/cm 2 in order to investigate their radiation hardness. The effects of irradiation on the electro-optical performance were monitored in dark condition and in the UV (200 ÷ 400 nm) range, as well as in the visible region confirming the typical visible blindness of unirradiated and irradiated SiC photo-sensors. A decrease of UV optical responsivity occurred after irradiation and two fluence regimes were identified. At low fluence (<10 13 ions/cm 2 ), a considerable reduction of optical responsivity (of about 50%) was measured despite the absence of relevant dark current changes. The presence of irradiation induced point defects and then the reduction of photo-generated charge lifetime are responsible for a reduction of the charge collection efficiency and then of the relevant optical response reduction: point defects act as recombination centers for the photo-generated charges, which recombine during the drift/diffusion toward the electrodes. At higher irradiation fluence, the optical responsivity is strongly reduced due to the formation of complex defects. The threshold between low and high fluence is about 100 kGy, confirming the radiation hardness of SiC photo-sensors.

This paper reports an investigation of the structural, chemical and electrical properties of ultra-thin (5 nm) aluminum nitride (AlN) films grown by plasma enhanced atomic layer deposition (PE-ALD) on gallium nitride (GaN). A uniform and conformal coverage of the GaN substrate was demonstrated by morphological analyses of as-deposited AlN films. Transmission electron microscopy (TEM) and energy dispersive spectroscopy (EDS) analyses showed a sharp epitaxial interface with GaN for the first AlN atomic layers, while a deviation from the perfect wurtzite stacking and oxygen contamination were detected in the upper part of the film. This epitaxial interface resulted in the formation of a two-dimensional electron gas (2DEG) with a sheet charge density n s ≈ 1.45 × 10 12 cm -2 , revealed by Hg-probe capacitance-voltage (C-V) analyses. Nanoscale resolution current mapping and current-voltage (I-V) measurements by conductive atomic force microscopy (C-AFM) showed a highly homogeneous current transport through the 5 nm AlN barrier, while a uniform flat-band voltage (V FB ≈ 0.3 V) for the AlN/GaN heterostructure was demonstrated by scanning capacitance microscopy (SCM). Electron transport through the AlN film was shown to follow the Fowler-Nordheim (FN) tunneling mechanism with an average barrier height of <Φ B > = 2.08 eV, in good agreement with the expected AlN/GaN conduction band offset.

Cancer stem cells (CSCs) play a key role in tumor initiation and progression. A real-time tool to evaluate the activation of CSC-specific signaling pathways is crucial for the study of this cancer cell subset. Here, we present a protocol to monitor, in vitro , the activation of Wnt/β-catenin signaling pathway, which is considered a functional biomarker for colorectal CSCs (CR-CSCs). This flow-cytometry-based protocol allows it to isolate CR-CSCs and to evaluate their cytotoxicity upon anti-tumor treatments. For complete details on the use and execution of this protocol, please refer to Di Franco et al. (2021)., Competing Interests: The authors declare no competing interests., (© 2021 The Authors.)

Colon cancer progression is among the risks that increase with obesity. We have recently unveiled the molecular mechanism by which adipose tissue-released molecules, HGF and IL-6, make colorectal cancer (CRC) cells acquiring mesenchymal traits. Targeting of adipose-derived factors abrogate the metastatic potential of CRC stem cells (CR-CSCs) in obese patients., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2021 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Obesity is a strong risk factor for cancer progression, posing obesity-related cancer as one of the leading causes of death. Nevertheless, the molecular mechanisms that endow cancer cells with metastatic properties in patients affected by obesity remain unexplored.Here, we show that IL-6 and HGF, secreted by tumor neighboring visceral adipose stromal cells (V-ASCs), expand the metastatic colorectal (CR) cancer cell compartment (CD44v6 + ), which in turn secretes neurotrophins such as NGF and NT-3, and recruits adipose stem cells within tumor mass. Visceral adipose-derived factors promote vasculogenesis and the onset of metastatic dissemination by activation of STAT3, which inhibits miR-200a and enhances ZEB2 expression, effectively reprogramming CRC cells into a highly metastatic phenotype. Notably, obesity-associated tumor microenvironment provokes a transition in the transcriptomic expression profile of cells derived from the epithelial consensus molecular subtype (CMS2) CRC patients towards a mesenchymal subtype (CMS4). STAT3 pathway inhibition reduces ZEB2 expression and abrogates the metastatic growth sustained by adipose-released proteins. Together, our data suggest that targeting adipose factors in colorectal cancer patients with obesity may represent a therapeutic strategy for preventing metastatic disease., (© 2021. The Author(s).)

Colorectal cancer (CRC) mortality is mainly caused by patient refractoriness to common anti-cancer therapies and consequent metastasis formation. Besides, the notorious toxic side effects of chemotherapy are a concurrent obstacle to be tackled. Thus, new treatment approaches are needed to effectively improve patient outcomes. Compelling evidence demonstrated that cancer stem cells (CSCs) are responsible for treatment failure and relapse. New natural treatment approaches showed capabilities to selectively target the CSC subpopulation by rendering them targetable by standard cytotoxic compounds. Herein we show the anti-cancer properties of the polymethoxyflavones and prenylflavonoids extracted from Citrus sinensis and Humulus lupulus , respectively. The natural biofunctional fractions, singularly and in combination, reduced the cell viability of CRC stem cells (CR-CSCs) and synergized with 5-fluorouracil and oxaliplatin (FOX) chemotherapy. These phenomena were accompanied by a reduced S and G2/M phase of the cell cycle and upregulation of cell death-related genes. Notably, both phytoextracts in combination with FOX thwarted stemness features in CR-CSCs as demonstrated by the impaired clonogenic potential and decreased Wnt pathway activation. Extracts lowered the expression of CD44v6 and affected the expansion of metastatic CR-CSCs in patients refractory to chemotherapy. Together, this study highlights the importance of polymethoxyflavones and prenylflavonoids as natural remedies to aid oncological therapies.

Despite the recent advances in cancer patient management and in the development of targeted therapies, systemic chemotherapy is currently used as a first-line treatment for many cancer types. After an initial partial response, patients become refractory to standard therapy fostering rapid tumor progression. Compelling evidence highlights that the resistance to chemotherapeutic regimens is a peculiarity of a subpopulation of cancer cells within tumor mass, known as cancer stem cells (CSCs). This cellular compartment is endowed with tumor-initiating and metastasis formation capabilities. CSC chemoresistance is sustained by a plethora of grow factors and cytokines released by neighboring tumor microenvironment (TME), which is mainly composed by adipocytes, cancer-associated fibroblasts (CAFs), immune and endothelial cells. TME strengthens CSC refractoriness to standard and targeted therapies by enhancing survival signaling pathways, DNA repair machinery, expression of drug efflux transporters and anti-apoptotic proteins. In the last years many efforts have been made to understand CSC-TME crosstalk and develop therapeutic strategy halting this interplay. Here, we report the combinatorial approaches, which perturb the interaction network between CSCs and the different component of TME., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Gaggianesi, Di Franco, Pantina, Porcelli, D'Accardo, Verona, Veschi, Colarossi, Faldetta, Pistone, Bongiorno, Todaro and Stassi.)

Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Background: Bloodstream infections (BSIs) constitute a growing public health concern, are among the most severe nosocomial pathologies, and are considered a worldwide cause of unfaithful outcomes, increasing treatment costs and diagnostic uncertainties. BSIs are one of the most frequent lethal conditions that are managed in intensive care units (ICUs). In the case of septic shock, immune deficiency, and delayed treatment, even with adequate antimicrobial therapy and/or source control, the outcomes are often unfavorable., Methods: this review article summarizes the epidemiological and microbiological characteristics of BSIs with a particular focus on ICU acquired BSIs (ICU-BSIs), which are usually caused by multidrug-resistant (MDR) pathogens. For this reason, their antimicrobial resistance patterns and therapeutic options have also been compiled., Results: ICU-acquired BSIs prevail in 5-7% of ICU patients. Klebsiella pneumoniae, Escherichia coli, Acinetobacter baumannii , and Pseudomonas aeruginosae are the pathogens most often responsible for MDR infections. MDR Enterobacteriaceae have seen their prevalence increase from 6.2% (1997-2000) to 15.8% (2013-2016) in recent years., Conclusions: Considering that prevention and treatment of sepsis is nowadays considered a global health priority by the World Health Organization, it is our obligation to invest more resources into solving or reducing the spread of these unfaithful infections. It is relevant to identify patients with risk factors that make them more susceptible to BSIs, to guarantee earlier molecular or microbiological diagnoses, and more rapidly appropriate treatment by using de-escalation strategies where possible.

Limited therapeutic options are available for advanced colorectal cancer (CRC). Herein, we report that exposure to a neo-synthetic bis(indolyl)thiazole alkaloid analog, nortopsentin 234 (NORA234), leads to an initial reduction of proliferative and clonogenic potential of CRC sphere cells (CR-CSphCs), followed by an adaptive response selecting the CR-CSphC-resistant compartment. Cells spared by the treatment with NORA234 express high levels of CD44v6, associated with a constitutive activation of Wnt pathway. In CR-CSphC-based organoids, NORA234 causes a genotoxic stress paralleled by G2-M cell cycle arrest and activation of CHK1, driving the DNA damage repair of CR-CSphCs, regardless of the mutational background, microsatellite stability, and consensus molecular subtype. Synergistic combination of NORA234 and CHK1 (rabusertib) targeting is synthetic lethal inducing death of both CD44v6-negative and CD44v6-positive CRC stem cell fractions, aside from Wnt pathway activity. These data could provide a rational basis to develop an effective strategy for the treatment of patients with CRC., Competing Interests: The authors have no conflicts of interests to declare., (© 2021 The Author(s).)

Cancer stem cells (CSCs) are the tumor cell subpopulation responsible for resistance to chemotherapy, tumor recurrence, and metastasis. An efficient therapy must act on low proliferating quiescent-CSCs (q-CSCs). We here investigate the effect of magnetic hyperthermia (MHT) in combination with local chemotherapy as a dual therapy to inhibit patient-derived colorectal qCR-CSCs. We apply iron oxide nanocubes as MHT heat mediators, coated with a thermoresponsive polymer (TR-Cubes) and loaded with DOXO (TR-DOXO) as a chemotherapeutic agent. The thermoresponsive polymer releases DOXO only at a temperature above 44 °C. In colony-forming assays, the cells exposed to TR-Cubes with MHT reveal that qCR-CSCs struggle to survive the heat damage and, with a due delay, restart the division of dormant cells. The eradication of qCR-CSCs with a complete stop of the colony formation was achieved only with TR-DOXO when exposed to MHT. The in vivo tumor formation study confirms the combined effects of MHT with heat-mediated drug release: only the group of animals that received the CR-CSCs pretreated, in vitro , with TR-DOXO and MHT lacked the formation of tumor even after several months. For DOXO-resistant CR-CSCs cells, the same results were shown, in vitro, when choosing the drug oxaliplatin rather than DOXO and applying MHT. These findings emphasize the potential of our nanoplatforms as an effective patient-personalized cancer treatment against qCR-CSCs.

In this study, 4H-SiC p-n junctions were irradiated with 700 keV He + ions in the fluence range 1.0 × 10 12 to 1.0 × 10 15 ions/cm 2 . The effects of irradiation were investigated by current-voltage (I-V) and capacitance-voltage (C-V) measurements, while deep-level transient spectroscopy (DLTS) was used to study the traps introduced by irradiation defects. Modifications of the device's electrical performances were observed after irradiation, and two fluence regimes were identified. In the low fluence range (≤10 13 ions/cm 2 ), I-V characteristics evidenced an increase in series resistance, which can be associated with the decrease in the dopant concentration, as also denoted by C-V measurements. In addition, the pre-exponential parameter of junction generation current increased with fluence due to the increase in point defect concentration. The main produced defect states were the Z 1/2 , RD 1/2 , and EH 6/7 centers, whose concentrations increased with fluence. At high fluence (>10 13 ions/cm 2 ), I-V curves showed a strong decrease in the generation current, while DLTS evidenced a rearrangement of defects. The detailed electrical characterization of the p-n junction performed at different temperatures highlights the existence of conduction paths with peculiar electrical properties introduced by high fluence irradiation. The results suggest the formation of localized highly resistive regions (realized by agglomeration of point defects) in parallel with the main junction.

The prognosis of locally advanced colorectal cancer (CRC) is currently unsatisfactory. This is mainly due to drug resistance, recurrence, and subsequent metastatic dissemination, which are sustained by the cancer stem cell (CSC) population. The main driver of the CSC gene expression program is Wnt signaling, and previous reports indicate that Wnt3a can activate p38 MAPK. Besides, p38 was shown to feed into the canonical Wnt/β-catenin pathway. Here we show that patient-derived locally advanced CRC stem cells (CRC-SCs) are characterized by increased expression of p38α and are "addicted" to its kinase activity. Of note, we found that stage III CRC patients with high p38α levels display reduced disease-free and progression-free survival. Extensive molecular analysis in patient-derived CRC-SC tumorspheres and APC Min/+ mice intestinal organoids revealed that p38α acts as a β-catenin chromatin-associated kinase required for the regulation of a signaling platform involved in tumor proliferation, metastatic dissemination, and chemoresistance in these CRC model systems. In particular, the p38α kinase inhibitor ralimetinib, which has already entered clinical trials, promoted sensitization of patient-derived CRC-SCs to chemotherapeutic agents commonly used for CRC treatment and showed a synthetic lethality effect when used in combination with the MEK1 inhibitor trametinib. Taken together, these results suggest that p38α may be targeted in CSCs to devise new personalized CRC treatment strategies.

Carbapenem antibiotics were first introduced in the 1980s and have long been considered the most active agents for the treatment of multidrug-resistant gram-negative bacteria. Over the last decade, carbapenem-resistant Enterobacteriaceae (CRE) have emerged as organisms causing spontaneous bacterial peritonitis. Infections caused by CRE have shown a higher mortality rate than those caused by bacteria sensitive to carbapenem antibiotics. Current antibiotic guidelines for the treatment of spontaneous bacterial peritonitis are insufficient, and rapid de-escalation of empiric antibiotic treatment is not widely recognized. This review summarizes the molecular characteristics, epidemiology and possible treatment of spontaneous bacterial peritonitis caused by CRE., Competing Interests: Conflict-of-interest statement: All authors declare no conflicts-of-interest related to this article., (©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.)

The pandemic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has garnered the attention of scientists worldwide in the search for an effective treatment while also focusing on vaccine development. Several drugs have been used for the management of coronavirus disease 2019 (COVID-19), which has affected many hospitals and health centers worldwide. Statistically significant results are lacking on the effectiveness of the experimented drugs in reducing COVID-19 morbidity or mortality, as there are very few published randomized clinical trials. Despite this, the literature offers some material for study and reflection. This opinion review attempts to address three burning questions on COVID-19 treatment options. (1) What kind of studies are currently published or ongoing in the treatment of patients with COVID-19? (2) What drugs are currently described in the literature as options of treatment for patients affected by the infection? And (3) Are there specific clinical manifestations related to COVID-19 that can be treated with a customized and targeted therapy? By answering these questions, we wish to create a summary of current COVID-19 treatments and the anti-COVID-19 treatments proposed in the recent clinical trials developed in the last 3 mo, and to describe examples of clinical manifestations of the SARS-CoV-2 infection with a cause-related treatment., Competing Interests: Conflict-of-interest statement: The authors declare no conflict of interest., (©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.)

Burn-induced compartment syndrome represents a serious and acute condition in deep circumferential burns of the extremities which, if left untreated, can cause severe complications. The surgical escharotomy that releases the high subdermal pressure is the therapeutic treatment of choice for burn-induced compartment syndrome. Guidelines for escharotomy indications and timing include pressure greater than 30 mm Hg and 6 Ps (Pain, Pallor, Paresthesia, Paralysis, Pulseless, and Poikilothermia). Nevertheless, despite the need for an early as possible pressure release, escharotomy is often delayed when a capable surgeon is not available, or if the indication is not completely clear to justify potential risks associated with surgical escharotomy. Early treatment of circumferential burns of the extremities with a Bromelain-based enzymatic agent NexoBrid® may represent a less traumatic and invasive procedure to reduce intra-compartmental pressure, replacing surgical escharotomy. This case study of 23 patients describes the variation of compartmental pressure in patients with circumferential burns of the extremities treated with NexoBrid® enzymatic escharotomy-debridement. All the patients were treated with NexoBrid® within 2 to 22 hours post-injury in our Burn Intensive Care Center. The excessive pressure recorded before treatment returned to normal below 30 mm Hg and an approximately 60% reduction of the compartmental pressure was observed in most cases within 1 hour from NXB application. On NexoBrid® removal after 4 hours complete debridement-escharotomy of the burns was achieved. Enzymatic escharotomy-debridement appears to be a useful and safe method to reduce postburn compartmental pressure. Additional randomized, well-controlled powered studies are needed to further support these results., (© The Author(s) 2020. Published by Oxford University Press on behalf of the American Burn Association. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: The purpose of this review is to evaluate the use and effectiveness of the local administration of tramadol in reducing post-operative pain during surgical interventions., Methods: The PubMed, EMBASE and Cochrane Central Register of Controlled Trials (CENTRAL) databases will be searched for this review. This systematic review will include studies evaluating the clinical efficacy of the local infiltration of tramadol, with no study design restrictions. Only studies that present clear descriptions of local tramadol administration are published in peer-reviewed journals in the English, Italian, Spanish, French, Portuguese or German language and are published in full will be taken into consideration. A meta-analysis will be performed when there is sufficient clinical homogeneity among the retrieved studies, and only randomized controlled studies and quasi-randomized controlled studies will be included. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach will be used to assess the certainty in the evidence. If a quantitative analysis cannot be conducted, a qualitative description of the results of the retrieved studies will be provided., Results: A high-quality synthesis of the current evidence on the local administration of tramadol for managing post-surgical pain will be illustrated using subjective reports and objective measures of performance. The primary outcomes will include the magnitude of post-operative pain intensity improvement, with improvement being as defined by a reduction by at least 2 points in the visual analogue scale (VAS) score or numerical rating scale (NRS) score. The secondary outcomes will be the magnitude of reduction in tramadol rescue doses and in other analgesic drug doses., Conclusion: This protocol will present evidence on the efficacy of tramadol in relieving post-surgical pain., Systemic Review Registration: PROSPERO CRD42018087381.

Ceftazidime-avibactam (CZA) is a novel beta-lactam beta-lactamase inhibitor combination approved for the treatment of complicated urinary tract infections, complicated intra-abdominal infections, and for hospital-acquired/ventilator-associated pneumonia. The aim of this systematic review (PROSPERO registration number: CRD42019128927) was to evaluate the effectiveness of CZA combination therapy versus CZA monotherapy in the treatment of severe infections. The databases included in the search, until February 12th, 2020, were MEDLINE by PubMed, EMBASE, and The Cochrane Central Register of Controlled Trials. We included both randomized controlled trials (RCTs) and non-randomized studies published in peer-reviewed journals and in the English language. The primary outcome was all-cause mortality (longest follow-up) evaluated in patients with the diagnosis of infection with at least one pathogen; secondary outcomes were clinical and microbiological improvement/cure. Thirteen studies were included in the qualitative synthesis: 7 RCTs and 6 retrospective studies All the six retrospective studies identified carbapenamase-producing Enterobacteriaceae (CRE) as the cause of infection and for this reason were included in the network meta-analysis (NMA); the quality of the studies, assessed using the New Castle-Ottawa Scale, was moderate-high. In all the six retrospective studies included in the NMA, CZA was used in large part for off-label indications (mostly blood stream infections: 80-100% of patients included). No difference in mortality rate was observed in patients undergoing CZA combination therapy compared to CZA monotherapy [ n = 503 patients, direct evidence OR: 0.96, 95% CI: 0.65-1.41]., Competing Interests: The authors declare no conflict of interest

The intestinal tract ( i.e ., the gut), is where the body's nutrients are absorbed, and is simultaneously inhabited by numerous microbes. An increasing body of literature suggests a crucial role for the gut microbiome in modulating systemic inflammatory disease. Psoriasis is a chronic systemic inflammatory disease and its pathogenesis is related to the interaction between genetic susceptibility, immune response and environmental triggers. The omics era has allowed physicians to assess different aspects of psoriasis pathogenesis such as the microbiome, infectome, and autoinfectome. Furthermore, diet appears to play an important role in modulating disease activity, perhaps by influencing gut microbes. Given these observations, we aimed to summarize the current knowledge regarding skin-microbiome-gut-nutrients and psoriasis., Competing Interests: Conflict-of-interest statement: The authors declare no conflict of interest., (©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.)

Our objective is to review the scientific literature on the use of antimicrobial lock therapy (ALT). To achieve this result, our scoping review will address the following seven key questions: 1) Who are the patients who will benefit from this technique? 2) What are the techniques utilized? 3) What are the settings in which the technique is performed? 4) When the technique is performed? 5) Why the technique is performed? 6) How the technique is performed? 7) In how much amount, of such technique performed? This review considers all studies published in full and in peer-reviewed journals, with no restrictions on language, on the year of publication and age of the participants. Both randomized controlled trials and observational studies will be included. This scoping review has been planned on a five-stage framework: 1. Identifying the review question; 2. identifying relevant studies; 3. study selection; 4. charting the data; 5. collating, summarizing, and reporting the results. It is conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Guidelines. The databases utilized will include MEDLINE via PubMed, EMBASE and Cochrane Central Register of Controlled Trials and Grey Literature. SCOPING REVIEW REGISTRATION: Open Science Framework https://osf.io/vphwm/., Competing Interests: All review authors disclose any potential conflict of interest, including any personal, financial, professional or intellectual bias.

Despite intense research and clinical efforts, patients affected by advanced colorectal cancer (CRC) have still a poor prognosis. The discovery of colorectal (CR) cancer stem cell (CSC) as the cell compartment responsible for tumor initiation and propagation may provide new opportunities for the development of new therapeutic strategies. Given the reduced sensitivity of CR-CSCs to chemotherapy and the ability of bone morphogenetic proteins (BMP) to promote colonic stem cell differentiation, we aimed to investigate whether an enhanced variant of BMP7 (BMP7v) could sensitize to chemotherapy-resistant CRC cells and tumors. Thirty-five primary human cultures enriched in CR-CSCs, including four from chemoresistant metastatic lesions, were used for in vitro studies and to generate CR-CSC-based mouse avatars to evaluate tumor growth and progression upon treatment with BMP7v alone or in combination with standard therapy or PI3K inhibitors. BMP7v treatment promotes CR-CSC differentiation and recapitulates the cell differentiation-related gene expression profile by suppressing Wnt pathway activity and reducing mesenchymal traits and survival of CR-CSCs. Moreover, in CR-CSC-based mouse avatars, BMP7v exerts an antiangiogenic effect and sensitizes tumor cells to standard chemotherapy regardless of the mutational, MSI, and CMS profiles. Of note, tumor harboring PIK3CA mutations were affected to a lower extent by the combination of BMP7v and chemotherapy. However, the addition of a PI3K inhibitor to the BMP7v-based combination potentiates PIK3CA-mutant tumor drug response and reduces the metastatic lesion size. These data suggest that BMP7v treatment may represent a useful antiangiogenic and prodifferentiation agent, which renders CSCs sensitive to both standard and targeted therapies.

This paper reports on the electrical activation and Ohmic contact properties on p-type Al-implanted silicon carbide (4H-SiC). In particular, the contacts were formed on 4H-SiC-implanted layers, subjected to three different post-implantation annealing processes, at 1675 °C, 1175 °C, and 1825 °C. Under these post-implantation annealing conditions, the electrical activation of the Al dopant species increased from 39% to 56%. The Ti/Al/Ni contacts showed an Ohmic behavior after annealing at 950 °C. The specific contact resistance ρ c could be lowered by a factor of 2.6 with the increase of the post-implantation annealing temperature. The result can be useful for application in device fabrication. Moreover, the dependence of ρ c on the active acceptor concentration followed the thermionic field emission model, with a barrier height of 0.63 eV.

Lipid Droplets (LDs) are emerging as crucial players in colon cancer development and maintenance. Their expression has been associated with high tumorigenicity in Cancer Stem Cells (CSCs), so that they have been proposed as a new functional marker in Colorectal Cancer Stem Cells (CR-CSCs). They are also indirectly involved in the modulation of the tumor microenvironment through the production of pro-inflammatory molecules. There is growing evidence that a possible connection between metabolic alterations and malignant transformation exists, although the effects of nutrients, primarily glucose, on the CSC behavior are still mostly unexplored. Glucose is an essential fuel for cancer cells, and the connections with LDs in the healthy and CSC populations merit to be more deeply investigated. Here, we showed that a high glucose concentration activated the PI3K/AKT pathway and increased the expression of CD133 and CD44v6 CSC markers. Additionally, glucose was responsible for the increased amount of Reactive Oxygen Species (ROS) and LDs in both healthy and CR-CSC samples. We also investigated the gene modulations following the HG treatment and found out that the healthy cell gene profile was the most affected. Lastly, Atorvastatin, a lipid-lowering drug, induced the highest mortality on CR-CSCs without affecting the healthy counterpart., Competing Interests: Authors declare no conflict of interest., (© 2019 Chongqing Medical University. Production and hosting by Elsevier B.V.)

Introduction : Spontaneous bacterial peritonitis (SBP) is a main infectious complication in end-stage liver disease (ESLD) patients. The increasing trend of bacterial resistance in ESLD patients with SBP has been associated with low treatment efficacy of traditional therapy. Cephalosporin use has been restricted to community-acquired infections and in areas/health care settings with low rates of multidrug-resistant (MDR) bacteria. To date, several changes are necessary with regard to empiric therapy recommendations in areas/health care settings with high rates of MDR bacteria. Areas covered : An overview of the epidemiology and antimicrobial treatments of SBP caused by Gram-negative bacteria. Expert opinion : Broad-spectrum antibiotics have been recommended as empiric therapy for suspected SBP in areas/health care settings with high rates of MDR bacteria and secondary treatment, with newer antibiotics, for SBP caused by MDR-Gram-negative bacteria (i.e. new beta-lactam/beta-lactamase inhibitor combinations, cefiderocol, plazomicin, and eravacycline) either alone or in combination.

Aim: To investigate the genome-wide methylation of genetically characterized colorectal cancer stem cell (CR-CSC) lines. Materials & methods: Eight CR-CSC lines were isolated from primary colorectal cancer (CRC) tissues, cultured and characterized for aneuploidy, mutational status of CRC-related genes and microsatellite instability (MSI). Genome-wide DNA methylation was assessed by MethylationEPIC microarray. Results: We describe a distinctive methylation pattern that is maintained following in vivo passages in immune-compromised mice. We identified an epigenetic CR-CSC signature associated with MSI. We noticed that the preponderance of the differentially methylated positions do not reside at CpG islands, but spread to shelf and open sea regions. Conclusion: Given that CRCs with MSI-high status have a lower metastatic potential, the identification of a MSI-related methylation signature could provide new insights and possible targets into metastatic CRC.

POEMS syndrome is a rare multisystemic disease characterised by the coexistence of two main symptoms, polyneuropathy and monoclonal gammopathy, associated with minor symptoms such as organomegaly, endocrinopathy, and skin changes. We describe a patient who presented with symptoms and signs fulfilling the criteria of POEMS. We have carried out a literature review with particular emphasis on its demographic and polymorphic clinical features., (Copyright by Società Italiana di Nefrologia SIN, Rome, Italy.)

In the last decades, the role of the microenvironment in tumor progression and therapeutic outcome has gained increasing attention. Cancer-associated fibroblasts (CAFs) have emerged as key players among stromal cells, owing to their abundance in most solid tumors and their diverse tumor-restraining/promoting roles. The interplay between tumor cells and neighboring CAFs takes place by both paracrine signals (cytokines, exosomes and metabolites) or by the multifaceted functions of the surrounding extracellular matrix. Here, we dissect the most recent identified mechanisms underlying CAF-mediated control of tumor progression and therapy resistance, which include induction of the epithelial-to-mesenchymal transition (EMT), activation of survival pathways or stemness-related programs and metabolic reprogramming in tumor cells. Importantly, the recently unveiled heterogeneity in CAFs claims tailored therapeutic efforts aimed at eradicating the specific subset facilitating tumor progression, therapy resistance and relapse. However, despite the large amount of pre-clinical data, much effort is still needed to translate CAF-directed anti-cancer strategies from the bench to the clinic.

Regenerative medicine is an emerging interdisciplinary field of scientific research that, supported by tissue engineering is, nowadays, a valuable and reliable solution dealing with the actual organs shortage and the unresolved limits of biological or prosthetic materials used in repair and replacement of diseased or damaged human tissues and organs. Due to the improvements in design and materials, and to the changing of clinical features of patients treated for valvular heart disease the distance between the ideal valve and the available prostheses has been shortened. We will then deal with the developing of new tools aiming at replacing or repair cardiac tissues that still represent an unmet clinical need for the surgeons and indeed for their patients. In the effort of improving treatment for the cardiovascular disease (CVD), scientists struggle with the lack of self-regenerative capacities of finally differentiated cardiovascular tissues. In this context, using several converging technological approaches, regenerative medicine moves beyond traditional transplantation and replacement therapies and can restore tissue impaired function. It may also play an essential role in surgery daily routine, leading to produce devices such as injectable hydrogels, cardiac patches, bioresorbable stents and vascular grafts made by increasingly sophisticated biomaterial scaffolds; tailored devices promptly fabricated according to surgeon necessity and patient anatomy and pathology will hopefully represent a daily activity in the next future. The employment of these devices, still far from the in vitro reproduction of functional organs, has the main aim to achieve a self-renewal process in damaged tissues simulating endogenous resident cell populations. In this field, the collaboration and cooperation between cardiothoracic surgeons and bioengineers appear necessary to modify these innovative devices employed in preclinical studies according to the surgeon's needs., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Objective: Cancer stem cells (CSCs) are responsible for tumour formation and spreading, and their targeting is required for tumour eradication. There are limited therapeutic options for advanced colorectal cancer (CRC), particularly for tumours carrying RAS-activating mutations. The aim of this study was to identify novel CSC-targeting strategies., Design: To discover potential therapeutics to be clinically investigated as single agent, we performed a screening with a panel of FDA-approved or investigational drugs on primary CRC cells enriched for CSCs (CRC-SCs) isolated from 27 patients. Candidate predictive biomarkers of efficacy were identified by integrating genomic, reverse-phase protein microarray (RPPA) and cytogenetic analyses, and validated by immunostainings. DNA replication stress (RS) was increased by employing DNA replication-perturbing or polyploidising agents., Results: The drug-library screening led to the identification of LY2606368 as a potent anti-CSC agent acting in vitro and in vivo in tumour cells from a considerable number of patients (∼36%). By inhibiting checkpoint kinase (CHK)1, LY2606368 affected DNA replication in most CRC-SCs, including RAS-mutated ones, forcing them into premature, lethal mitoses. Parallel genomic, RPPA and cytogenetic analyses indicated that CRC-SCs sensitive to LY2606368 displayed signs of ongoing RS response, including the phosphorylation of RPA32 and ataxia telangiectasia mutated serine/threonine kinase (ATM). This was associated with mutation(s) in TP53 and hyperdiploidy, and made these CRC-SCs exquisitely dependent on CHK1 function. Accordingly, experimental increase of RS sensitised resistant CRC-SCs to LY2606368., Conclusions: LY2606368 selectively eliminates replication-stressed, p53-deficient and hyperdiploid CRC-SCs independently of RAS mutational status. These results provide a strong rationale for biomarker-driven clinical trials with LY2606368 in patients with CRC., Competing Interests: Competing interests: None declared., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Background: The use of stem cells, including mesenchymal stem cells (MSCs), for regenerative medicine is gaining interest for the clinical benefits so far obtained in patients. This study investigates the use of adipose autologous tissue in combination with platelet-rich plasma (PRP) to improve the clinical outcome of patients affected by systemic sclerosis (SSc)., Methods: Adipose-derived mesenchymal stem cells (AD-MSCs) and PRPs were purified from healthy donors and SSc patients. The multilineage differentiation potential of AD-MSCs and their genotypic-phenotypic features were investigated. A cytokine production profile was evaluated on AD-MSCs and PRPs from both healthy subjects and SSc patients. The adipose tissue-derived cell fraction, the so-called stromal vascular fraction (SVF), was coinjected with PRP in the perioral area of SSc patients., Results: Histopathological and phenotypical analysis of adipose tissue from SSc patients revealed a disorganization of its distinct architecture coupled with an altered cell composition. Although AD-MSCs derived from SSc patients showed high multipotency, they failed to sustain a terminally differentiated progeny. Furthermore, SVFs derived from SSc patients differed from healthy donors in their MSC-like traits coupled with an aberrant cytokine production profile. Finally, the administration of PRP in combination with autologous SVF improved buccal's rhyme, skin elasticity and vascularization for all of the SSc patients enrolled in this study., Conclusions: This innovative regenerative therapy could be exploited for the treatment of chronic connective tissue diseases, including SSc.

Cancer can be considered an aberrant organ with a hierarchical composition of different cell populations. The tumor microenvironment, including the immune cells and related cytokines, is crucial during all the steps of tumor development. In particular, type I and II interferons (IFNs) are involved in a plethora of mechanisms that regulate immune responses in cancer, thus balancing immune escape versus immune surveillance. IFNs are involved in both the direct and indirect regulation of cancer cell proliferation and metastatic potential. The mutational background of genes involved in IFNs signaling could serve as a prognostic biomarker and a powerful tool to screen cancer patients eligible for checkpoint blocking therapies. We herewith describe the latest findings regarding the contribution of IFNs in colorectal cancer and melanoma by researching their dual role as either tumor promoter or suppressor, in diverse tumor types, and microenvironmental context. We are reporting the most innovative and promising approaches of IFN-based therapies that have achieved considerable outcomes in clinical oncology practice and explain the possible mechanisms responsible for their failure.

One of the main challenges to exploit molybdenum disulfide (MoS 2 ) potentialities for the next-generation complementary metal oxide semiconductor (CMOS) technology is the realization of p-type or ambipolar field-effect transistors (FETs). Hole transport in MoS 2 FETs is typically hampered by the high Schottky barrier height (SBH) for holes at source/drain contacts, due to the Fermi level pinning close to the conduction band. In this work, we show that the SBH of multilayer MoS 2 surface can be tailored at nanoscale using soft O 2 plasma treatments. The morphological, chemical, and electrical modifications of MoS 2 surface under different plasma conditions were investigated by several microscopic and spectroscopic characterization techniques, including X-ray photoelectron spectroscopy (XPS), atomic force microscopy (AFM), conductive AFM (CAFM), aberration-corrected scanning transmission electron microscopy (STEM), and electron energy loss spectroscopy (EELS). Nanoscale current-voltage mapping by CAFM showed that the SBH maps can be conveniently tuned starting from a narrow SBH distribution (from 0.2 to 0.3 eV) in the case of pristine MoS 2 to a broader distribution (from 0.2 to 0.8 eV) after 600 s O 2 plasma treatment, which allows both electron and hole injection. This lateral inhomogeneity in the electrical properties was associated with variations of the incorporated oxygen concentration in the MoS 2 multilayer surface, as shown by STEM/EELS analyses and confirmed by ab initio density functional theory (DFT) calculations. Back-gated multilayer MoS 2 FETs, fabricated by self-aligned deposition of source/drain contacts in the O 2 plasma functionalized areas, exhibit ambipolar current transport with on/off current ratio I on /I off ≈ 10 3 and field-effect mobilities of 11.5 and 7.2 cm 2 V -1 s -1 for electrons and holes, respectively. The electrical behavior of these novel ambipolar devices is discussed in terms of the peculiar current injection mechanisms in the O 2 plasma functionalized MoS 2 surface.

The tumor microenvironment supplies proinflammatory cytokines favoring a permissive milieu for cancer cell growth and invasive behavior. Here we show how breast cancer progression is facilitated by IL4 secreted by adipose tissue and estrogen receptor-positive and triple-negative breast cancer cell types. Blocking autocrine and paracrine IL4 signaling with the IL4Rα antagonist IL4DM compromised breast cancer cell proliferation, invasion, and tumor growth by downregulating MAPK pathway activity. IL4DM reduced numbers of CD44 + /CD24 - cancer stem-like cells and elevated expression of the dual specificity phosphatase DUSP4 by inhibiting NF-κB. Enforced expression of DUSP4 drove conversion of metastatic cells to nonmetastatic cells. Mechanistically, RNAi-mediated attenuation of DUSP4 activated the ERK and p38 MAPK pathways, increased stem-like properties, and spawned metastatic capacity. Targeting IL4 signaling sensitized breast cancer cells to anticancer therapy and strengthened immune responses by enhancing the number of IFNγ-positive CTLs. Our results showed the role of IL4 in promoting breast cancer aggressiveness and how its targeting may improve the efficacy of current therapies. Cancer Res; 77(12); 3268-79. ©2017 AACR ., (©2017 American Association for Cancer Research.)

High-quality thin insulating films on graphene (Gr) are essential for field-effect transistors (FETs) and other electronics applications of this material. Atomic layer deposition (ALD) is the method of choice to deposit high-κ dielectrics with excellent thickness uniformity and conformal coverage. However, to start the growth on the sp 2 Gr surface, a chemical prefunctionalization or the physical deposition of a seed layer are required, which can effect, to some extent, the electrical properties of Gr. In this paper, we report a detailed morphological, structural, and electrical investigation of Al 2 O 3 thin films grown by a two-steps ALD process on a large area Gr membrane residing on an Al 2 O 3 -Si substrate. This process consists of the H 2 O-activated deposition of a Al 2 O 3 seed layer a few nanometers in thickness, performed in situ at 100 °C, followed by ALD thermal growth of Al 2 O 3 at 250 °C. The optimization of the low-temperature seed layer allowed us to obtain a uniform, conformal, and pinhole-free Al 2 O 3 film on Gr by the second ALD step. Nanoscale-resolution mapping of the current through the dielectric by conductive atomic force microscopy (CAFM) demonstrated an excellent laterally uniformity of the film. Raman spectroscopy measurements indicated that the ALD process does not introduce defects in Gr, whereas it produces a partial compensation of Gr unintentional p-type doping, as confirmed by the increase of Gr sheet resistance (from ∼300 Ω/sq in pristine Gr to ∼1100 Ω/sq after Al 2 O 3 deposition). Analysis of the transfer characteristics of Gr field-effect transistors (GFETs) allowed us to evaluate the relative dielectric permittivity (ε = 7.45) and the breakdown electric field (E BD = 7.4 MV/cm) of the Al 2 O 3 film as well as the transconductance and the holes field-effect mobility (∼1200 cm 2 V -1 s -1 ). A special focus has been given to the electrical characterization of the Al 2 O 3 -Gr interface by the analysis of high frequency capacitance-voltage measurements, which allowed us to elucidate the charge trapping and detrapping phenomena due to near-interface and interface oxide traps.

Graphene is an ideal candidate for next generation applications as a transparent electrode for electronics on plastic due to its flexibility and the conservation of electrical properties upon deformation. More importantly, its field-effect tunable carrier density, high mobility and saturation velocity make it an appealing choice as a channel material for field-effect transistors (FETs) for several potential applications. As an example, properly designed and scaled graphene FETs (Gr-FETs) can be used for flexible high frequency (RF) electronics or for high sensitivity chemical sensors. Miniaturized and flexible Gr-FET sensors would be highly advantageous for current sensors technology for in vivo and in situ applications. In this paper, we report a wafer-scale processing strategy to fabricate arrays of back-gated Gr-FETs on poly(ethylene naphthalate) (PEN) substrates. These devices present a large-area graphene channel fully exposed to the external environment, in order to be suitable for sensing applications, and the channel conductivity is efficiently modulated by a buried gate contact under a thin Al 2 O 3 insulating film. In order to be compatible with the use of the PEN substrate, optimized deposition conditions of the Al 2 O 3 film by plasma-enhanced atomic layer deposition (PE-ALD) at a low temperature (100 °C) have been developed without any relevant degradation of the final dielectric performance.

Molybdenum disulphide (MoS 2 ) is currently regarded as a promising material for the next generation of electronic and optoelectronic devices. However, several issues need to be addressed to fully exploit its potential for field effect transistor (FET) applications. In this context, the contact resistance, R C , associated with the Schottky barrier between source/drain metals and MoS 2 currently represents one of the main limiting factors for suitable device performance. Furthermore, to gain a deeper understanding of MoS 2 FETs under practical operating conditions, it is necessary to investigate the temperature dependence of the main electrical parameters, such as the field effect mobility (μ) and the threshold voltage ( V th ). This paper reports a detailed electrical characterization of back-gated multilayer MoS 2 transistors with Ni source/drain contacts at temperatures from T = 298 to 373 K, i.e., the expected range for transistor operation in circuits/systems, considering heating effects due to inefficient power dissipation. From the analysis of the transfer characteristics ( I D - V G ) in the subthreshold regime, the Schottky barrier height (Φ B ≈ 0.18 eV) associated with the Ni/MoS 2 contact was evaluated. The resulting contact resistance in the on-state (electron accumulation in the channel) was also determined and it was found to increase with T as R C proportional to T 3.1 . The contribution of R C to the extraction of μ and V th was evaluated, showing a more than 10% underestimation of μ when the effect of R C is neglected, whereas the effect on V th is less significant. The temperature dependence of μ and V th was also investigated. A decrease of μ proportional to 1/ T α with α = 1.4 ± 0.3 was found, indicating scattering by optical phonons as the main limiting mechanism for mobility above room temperature. The value of V th showed a large negative shift (about 6 V) increasing the temperature from 298 to 373 K, which was explained in terms of electron trapping at MoS 2 /SiO 2 interface states.

Radiotherapy is based on the induction of lethal DNA damage, primarily DNA double-strand breaks (DSB). Efficient DSB repair via Non-Homologous End Joining or Homologous Recombination can therefore undermine the efficacy of radiotherapy. By suppressing DNA-DSB repair with hyperthermia (HT) and DNA-PKcs inhibitor NU7441 (DNA-PKcsi), we aim to enhance the effect of radiation.The sensitizing effect of HT for 1 hour at 42°C and DNA-PKcsi [1 μM] to radiation treatment was investigated in cervical and breast cancer cells, primary breast cancer sphere cells (BCSCs) enriched for cancer stem cells, and in an in vivo human tumor model. A significant radio-enhancement effect was observed for all cell types when DNA-PKcsi and HT were applied separately, and when both were combined, HT and DNA-PKcsi enhanced radio-sensitivity to an even greater extent. Strikingly, combined treatment resulted in significantly lower survival rates, 2 to 2.5 fold increase in apoptosis, more residual DNA-DSB 6 h post treatment and a G2-phase arrest. In addition, tumor growth analysis in vivo showed significant reduction in tumor growth and elevated caspase-3 activity when radiation was combined with HT and DNA-PKcsi compared to radiation alone. Importantly, no toxic side effects of HT or DNA-PKcsi were found.In conclusion, inhibiting DNA-DSB repair using HT and DNA-PKcsi before radiotherapy leads to enhanced cytotoxicity in cancer cells. This effect was even noticed in the more radio-resistant BCSCs, which are clearly sensitized by combined treatment. Therefore, the addition of HT and DNA-PKcsi to conventional radiotherapy is promising and might contribute to more efficient tumor control and patient outcome.

P63 is a transcription factor belonging to the family of p53, essential for the development and differentiation of epithelia. In recent years, it has become clear that altered expression of the different isoforms of this gene can play an important role in carcinogenesis. The p63 gene encodes for two main isoforms known as TA and ΔN p63 with different functions. The role of these different isoforms in sustaining tumor progression and metastatic spreading however has not entirely been clarified. Here we show that breast cancer initiating cells express ΔNp63 isoform that supports a more mesenchymal phenotype associated with a higher tumorigenic and metastatic potential. On the contrary, the majority of cells within the tumor appears to express predominantly TAp63 isoform. While ΔNp63 exerts its effects by regulating a PI3K/CD44v6 pathway, TAp63 modulates this pathway in an opposite fashion. As a result, tumorigenicity and invasive capacity of breast cancer cells is a balance of the two isoforms. Finally, we found that tumor microenvironmental cytokines significantly contribute to the establishment of breast cancer cell phenotype by positively regulating ΔNp63 and CD44v6 expression.

In this paper, nanoscale resolution scanning capacitance microscopy (SCM) and local capacitance-voltage measurements were used to probe the interfacial donor concentration in SiO2/4H-SiC systems annealed in N2O. Such nitrogen-based annealings are commonly employed to passivate SiO2/SiC interface traps, and result both in the incorporation of N-related donors in SiC and in the increase of the mobility in the inversion layer in 4H-SiC MOS-devices. From our SCM measurements, a spatially inhomogeneous donor distribution was observed in the SiO2/4H-SiC system subjected to N2O annealing. Hence, the effect of a phosphorus implantation before the oxide deposition and N2O annealing was also evaluated. In this case, besides an increased average donor concentration, an improvement of the lateral homogeneity of the active doping was also detected. The possible implications of such a pre-implantation doping of the near-interface region on 4H-SiC MOS-devices are discussed.

Cancer stem cells (CSCs) are considered to be the origin of cancer and it is suggested that they are resistant to chemotherapy. Current therapies fail to eradicate CSCs and therefore selecting a resistant cell subset that is able to facilitate tumor recurrences. Betulinic acid (BetA) is a broad acting natural compound, shown to induce cell death via the inhibition of the stearoyl-CoA- desaturase (SCD- 1). This enzyme converts saturated fatty acids into unsaturated fatty acids and is over-expressed in tumor cells. Here we show that BetA induces rapid cell death in all colon CSCs tested and is able to affect the CSCs directly as shown, via the loss of clonogenic capacity. Similar results were observed with inhibition of SCD-1, suggesting that SCD-1 activity is indeed a vulnerable link in colon CSCs and can be considered an ideal target for therapy in colon cancer.

The cancer stem cell (CSC) model is describing tumors as a hierarchical organized system and CSCs are suggested to be responsible for cancer recurrence after therapy. The identification of specific markers of CSCs is therefore of paramount importance. Here, we show that high levels of lipid droplets (LDs) are a distinctive mark of CSCs in colorectal (CR) cancer. This increased lipid content was clearly revealed by label-free Raman spectroscopy and it directly correlates with well-accepted CR-CSC markers as CD133 and Wnt pathway activity. By xenotransplantation experiments, we have finally demonstrated that CR-CSCs overexpressing LDs retain most tumorigenic potential. A relevant conceptual advance in this work is the demonstration that a cellular organelle, the LD, is a signature of CSCs, in addition to molecular markers. A further functional characterization of LDs could lead soon to design new target therapies against CR-CSCs., (© 2014 The Authors. STEM CELLS Published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.)

The mutual and interdependent interaction between tumor and its microenvironment is a crucial topic in cancer research. Recently, it was reported that targeting stromal events could improve efficacies of current therapeutics and prevent metastatic spreading. Tumor microenvironment is a "complex network" of different cell types, soluble factors, signaling molecules and extracellular matrix components, which orchestrate the fate of tumor progression. As by definition, cancer stem cells (CSCs) are proposed to be the unique cell type able to maintain tumor mass and survive outside the primary tumor at metastatic sites. Being exposed to environmental stressors, including reactive oxygen species (ROS), CSCs have developed a GSH-dependent antioxidant system to improve ROS defense capability and acquire a malignant phenotype. Nevertheless, tumor progression is dependent on extracellular matrix remodeling, fibroblasts and macrophages activation in response to oxidative stress, as well as epithelial mesenchymal transition (EMT)-inducing signals and endothelial and perivascular cells recruitment. Besides providing a survival advantage by inducing de novo angiogenesis, tumor-associated vessels contribute to successful dissemination by facilitating tumor cells entry into the circulatory system and driving the formation of pre-metastatic niche. In this review, we focus on the synergistic effect of hypoxia inducible factors (HIFs) and vascular endothelial growth factors (VEGFs) in the successful outgrowth of metastasis, integrating therefore many of the emerging models and theories in the field., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Chemical vapour deposition (CVD) on catalytic metals is one of main approaches for high-quality graphene growth over large areas. However, a subsequent transfer step to an insulating substrate is required in order to use the graphene for electronic applications. This step can severely affect both the structural integrity and the electronic properties of the graphene membrane. In this paper, we investigated the morphological and electrical properties of CVD graphene transferred onto SiO2 and on a polymeric substrate (poly(ethylene-2,6-naphthalene dicarboxylate), briefly PEN), suitable for microelectronics and flexible electronics applications, respectively. The electrical properties (sheet resistance, mobility, carrier density) of the transferred graphene as well as the specific contact resistance of metal contacts onto graphene were investigated by using properly designed test patterns. While a sheet resistance R sh ≈ 1.7 kΩ/sq and a specific contact resistance ρc ≈ 15 kΩ·μm have been measured for graphene transferred onto SiO2, about 2.3× higher R sh and about 8× higher ρc values were obtained for graphene on PEN. High-resolution current mapping by torsion resonant conductive atomic force microscopy (TRCAFM) provided an insight into the nanoscale mechanisms responsible for the very high ρc in the case of graphene on PEN, showing a ca. 10× smaller "effective" area for current injection than in the case of graphene on SiO2.

Tumor cell populations have been recently proposed to be composed of two compartments: tumor-initiating cells characterized by a slow and asymmetrical growth, and the "differentiated" cancer cells with a fast and symmetrical growth. Cancer stem cells or cancer-initiating cells (CICs) play a crucial role in tumor recurrence. The resistance of CICs to drugs and irradiation often allows them to survive traditional therapy. NK cells are potent cytotoxic lymphocytes that can recognize tumor cells. In this study, we have analyzed the NK cell recognition of tumor target cells derived from the two cancer cell compartments of colon adenocarcinoma lesions. Our data demonstrate that freshly purified allogeneic NK cells can recognize and kill colorectal carcinoma-derived CICs whereas the non-CIC counterpart of the tumors (differentiated tumor cells), either autologous or allogeneic, is less susceptible to NK cells. This difference in the NK cell susceptibility correlates with higher expression on CICs of ligands for NKp30 and NKp44 in the natural cytotoxicity receptor (NCR) group of activating NK receptors. In contrast, CICs express lower levels of MHC class I, known to inhibit NK recognition, on their surface than do the "differentiated" tumor cells. These data have been validated by confocal microscopy where NCR ligands and MHC class I molecule membrane distribution have been analyzed. Moreover, NK cell receptor blockade in cytotoxicity assays demonstrates that NCRs play a major role in the recognition of CIC targets. This study strengthens the idea that biology-based therapy harnessing NK cells could be an attractive opportunity in solid tumors.

Tumor-initiating cells are responsible for tumor maintenance and relapse in solid and hematologic cancers. Although tumor-initiating cells were initially believed to be mainly quiescent, rapidly proliferating tumorigenic cells were found in breast cancer. In colon cancer, the proliferative activity of the tumorigenic population has not been defined, although it represents an essential parameter for the development of more effective therapeutic strategies. Here, we show that tumorigenic colon cancer cells can be found in a rapidly proliferating state in vitro and in vivo, both in human tumors and mouse xenografts. Inhibitors of polo-like kinase1 (Plk1), a mitotic kinase essential for cell proliferation, demonstrated maximal efficiency over other targeted compounds and chemotherapeutic agents in inducing death of colon cancer-initiating cells in vitro. In vivo, Plk1 inhibitors killed CD133(+) colon cancer cells leading to complete growth arrest of colon cancer stem cell-derived xenografts, whereas chemotherapeutic agents only slowed tumor progression. While chemotherapy treatment increased CD133(+) cell proliferation, treatment with Plk1 inhibitors eliminated all proliferating tumor-initiating cells. Quiescent CD133(+) cells that survived the treatment with Plk1 inhibitors could be killed by subsequent Plk1 inhibition when they exited from quiescence. Altogether, these results provide a new insight into the proliferative status of colon tumor-initiating cells both in basal conditions and in response to therapy and indicate Plk1 inhibitors as potentially useful in the treatment of colorectal cancer., (Copyright © 2012 AlphaMed Press.)