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Abstract Advances in bladder cancer (BCa) treatment have been hampered by the lack of predictive biomarkers and targeted therapies. Here, we demonstrate that loss of the tumor suppressor NUMB promotes aggressive bladder tumorigenesis and worsens disease outcomes. Retrospective cohort studies show that NUMB-loss correlates with poor prognosis in post-cystectomy muscle-invasive BCa patients and increased risk of muscle invasion progression in non-muscle invasive BCa patients. In mouse models, targeted Numb ablation induces spontaneous tumorigenesis and sensitizes the urothelium to carcinogenic insults, accelerating tumor onset and progression. Integrative transcriptomic and functional analyses in mouse and human BCa models reveal that upregulation of YAP transcriptional activity via a RHOA/ROCK-dependent pathway is a hallmark of NUMB-deficient BCa. Pharmacological or genetic inhibition of this molecular pathway selectively inhibits proliferation and invasion of NUMB-deficient BCa cells in 3D-Matrigel organoids. Thus, NUMB-loss could serve as a biomarker for identifying high-risk patients who may benefit from targeted anti-RHOA/ROCK/YAP therapies.

Finding biomarkers for targeted therapy is a promising approach to treat cancer. Here, the authors show that in breast cancer preclinical models and patients, CDK12 promotes tumourigenesis but induces selective vulnerability to therapies that target folate one-carbon metabolism.

ABSTRACT Various attributes are often required to build soil quality indicators. However, determining these attributes is time-consuming and requires several specific devices. Thus, it is desirable to develop indexes that express soil quality based on easily determined attributes. The objective of this study was to investigate the spatial variability of the S index and its correlation with other physical and chemical soil attributes to generate a pedotransfer function for estimating the S index. A georeferenced sampling mesh covering 1.4 ha and employing 71 points was installed. The soil samples were collected in 0.00–0.15 m and 0.15–0.30 m deep layers to determine the physical and chemical attributes. The results indicated that the S index was correlated with porosity, carbon stocks, cation exchange capacity, and particle size fractions. However, macroporosity, microporosity, and sand content were the most suitable attributes for the construction of pedotransfer functions. A principal component analysis indicated that the S index was representative of 9.4% and 11.5% of the total variability in the dataset in the respective soil layers. Spherical semivariogram models showed that the S index was spatially dependent and ranged between 84–188 m. The S index maps estimated by the pedotransfer function resemble the observed S values; therefore, the function can be applied in spatial variability studies.

ABSTRACT The least limiting water range (LLWR) is a soil physical quality indicator that receives much attention. It has been criticized and put to the test regarding mathematical models that compose it since they describe the behavior of soil physical attributes in a simplified way. This study aimed to assess the efficiency of some pedofunctions proposed in the literature and artificial neural networks on the accuracy in predicting soil water retention at potentials equivalent to field capacity (θFC) and permanent wilting point (θPWP). In other words, to apply the best models to LLWR of two soil types (Oxisol and Ultisol) and verify changes in their structure. The results indicated that pedofunctions using sand, silt, clay, bulk density, and soil organic matter contents are more efficient in estimating θFC and θPWP. However, the use of multiple linear regression models to predict θFC values below 0.20 m3 m−3 may present a slight tendency to overestimate it, which is not observed in the neural networks. As in R2, equations from neural networks were more efficient in estimating θFC and θPWP. Pedofunctions used to calculate LLWR differ in the establishment of the critical soil bulk density, exposing the limitations of the model.

ABSTRACT Assess the physical quality of agricultural soils it is important to establish the management more adequate for plant growth. In this study, the soil water retention curve and S index as indicators of soil physical quality were evaluated in five integrated production systems in the following forestry arrangements: Eucalyptus in a single line, double line and triple line (Eucalyptus I, II and III respectively), Balsa in triple line and Teak triple line. The density and arrangement of forest trees influence the soil physical properties. Less soil water retention was observed in the Teak and Balsa wood systems in the layers 0-0.10 and 0.10-0.20 m. The field capacity, permanent wilting point, and available water were lower under the projection from the treetops, providing less soil water retention at this site. This position suffers more influence of the animal's footstep, having greater alterations on the soil structure. Integrated production systems showed poor soil structural quality based on the S index, averaging 0.034 and 0.035 for layers 0-0.10 and 0.10-0.20 m respectively.

The present study aimed to study the effect of different cover crops on grain discoloration severity and upland rice yield in order to make recommendations for agricultural practices that provide better performances. The experiment was carried out in the crop year 2011/2012 in Santa Carmen, northern state of Mato Grosso, Brasil, in an Oxisol that has been cultivated under the integrated crop-livestock systems for six years. The treatments were T1: intercropping system with cowpea (Vigna unguiculata) and Brachiaria ruziziensis, T2: intercropping system with Crotalaria ochroleuca and B. ruziziensis and T3 intercropping system with Sudan grass (Sorghum sudanense) and B. ruziziensis. The grain discoloration disease was responsible for 34% reduction in yield and a 10% reduction in weight of 100 grains. The results showed significant differences in treatment effects on grain yield, weight of 100 grains and grain discoloration severity. The intercropping system of previous crops that provided better yields and lower disease severity was that of B. ruziziensis and cowpea, being the most suitable to compose the system of crop rotation before planting rice.

O experimento foi realizado em ambiente protegido, com o objetivo de avaliar o efeito do resíduo da mineração de bauxita nos teores de macronutrientes, no solo e em plantas de cana-de-açúcar. Foram utilizados vasos de 10 L que receberam as seguintes doses de resíduo de bauxita: 0; 28;56; 84; 112 e 140 t ha-1, utilizando-se do clone de cana-de-açúcar SP92 4221. A incorporação do resíduo de bauxita no solo proporcionou aumento nos teores dos macronutrientes do solo, sendo que apenas para o enxofre doses acima de 83 t ha-1 proporcionaram reduções desse nutriente. Já para os teores de macronutrientes determinados na folha, doses acima de 70,5; 125; 101 e 56 t ha-1 diminuíram os teores de nitrogênio, fósforo, potássio e enxofre, respectivamente. Entretanto, para o cálcio e o magnésio, a utilização do resíduo proporcionou a diminuição dos seus teores foliares. A dose do resíduo de bauxita que teve a maior produção de massa seca foi de 64 t ha-1.The experiment was carried out in green house with the objective of evaluating the effect of the bauxite mining residue in the rates of macronutrients in sugarcane and soil. Containers of 10 L were used. They received the following rates of bauxite residue: 0; 28; 56; 84; 112 and 140 t ha-1 . The used culture was the sugarcane (SP92 4221). The incorporation of the bauxite residue in the soil provided an increase in the levels of the soil macronutrients, and only for sulphur levels above 83 t ha-1, it was possible to provide reductions of this nutrient. For rates of determined macronutrients in the leaf, levels above 70, 5; 125; 101; 56 t ha -1 diminished the rates of nitrogen, phosphorum, potassium and sulphur, respectively. However, for calcium and magnesium the use of the residue provided the reduction of leaf rates. The level of the bauxite residue which had the largest production of dry mass was 64 t ha-1.

A resistência mecânica do solo à penetração exerce grande influência sobre o desenvolvimento vegetal, uma vez que o crescimento das raízes e a produtividade das culturas variam de forma inversamente proporcional ao seu valor. O objetivo do trabalho foi estudar a variabilidade espacial e a correlação entre a produtividade do milho (PG) e a resistência mecânica do solo à penetração (RP) de um Latossolo Vermelho sob preparo convencional, em área pertencente à Fazenda Experimental de Ensino e Pesquisa da Faculdade de Engenharia - FE/UNESP - Câmpus de Ilha Solteira. Foram definidos 133 pontos de amostragem no campo, segundo malha com espaçamento regular de 10,0 m, nos quais foram medidas a RP, a umidade gravimétrica (UG), nas camadas de 0-0,10; 0,10-0,20; 0,20-0,30 e 0,30-0,40 m, e a PG. O modelo exponencial mostrou-se adequado para descrever todos os semivariogramas experimentais construídos. A RP e a UG apresentaram moderada dependência espacial, com alcance variando entre 20,2 e 63,0 m. A PG apresentou forte dependência espacial com alcance de 15,3 m. A RP não apresentou correlação espacial com a PG. Valores de RP variando entre 0,9 e 2,0 MPa não restringiram a PG.The soil mechanical resistance to penetration shows high influence on vegetal development since the growth of the roots and the crops productivity change in the inversely proportional form with its value. The objective was to study the spatial variability and the correlation between maize yield (GP) and soil mechanical resistance to penetration (PR) of an Oxissol soil under conventional tillage, located at the Experimental Station of the Engineering College - FE/UNESP - Ilha Solteira, São Paulo State, Brazil. It was defined 133 points of sampling in the field, according to a grid with regular intervals of 10.0 m, for the attainment of PR, gravimetric moisture (GM), in the layers of 0-0.10; 0.10-0.20; 0.20-0.30 and 0.30-0.40 m, and the GP. The exponential model showed adequate to describe all the adjusted experimental semivariograms. The PR and GM showed moderate spatial dependence, with range varying between 20.2 to 63.0 m. The GP presented strong spatial dependence with range of 15.3 m. There was not a spatial correlation between PR and GP. Values of PR varying between 0.9 and 2.0 MPa did not limit the GP.

Foi pesquisada a variabilidade espacial de alguns atributos físicos e químicos de uma associação de solos cultivada sob videira (Vitis vinifera-L), do município de Vitória Brasil, estado de São Paulo, Brasil. O objetivo foi estudar a dependência espacial de tais atributos, assim como caracterizar as respectivas variabilidades, distribuições de freqüência e números mínimos de subamostras do solo para a cultura da videira. Para isso, coletaram-se dados do solo, dispostos segundo uma malha com 156 pontos amostrais, sendo analisados por meio da geoestatística. As maiores variabilidades foram verificadas para a macroporosidade (MA), P, K, Ca, Mg, SB e CTC, ao passo que as menores foram para a densidade do solo (DS), pH e V. O número mínimo de subamostras, necessário para formar uma amostra composta e representativa, variou de 1 (pH e V) a 241 (Mg), tendo seu valor médio de 64 subamostras. Quanto à dependência espacial, o P e o V apresentaram, respectivamente, forte e fraca dependência, enquanto o restante dos atributos apresentou moderada dependência. Desta forma, o alcance dos atributos físicos variou de 2,56 a 4,32 m, enquanto o dos químicos variou de 1,82 a 5,64 m.The spatial variability of some physical and chemical characteristics of a compound of soils under grapevine (Vitis vinifera-L) cultivation was studied in the county Vitória Brasil, State of Sao Paulo, Brazil. Main objective was research into the spatial dependence of these soil characteristics and their variability, frequency distribution and minimum number of soil subsamples for grapevine crop. Soil data were collected in grid sampling at 156 points, using geoestatistics for the data analysis. Highest variability was found for macroporosity (MA), P, K, Ca, Mg, SB, and CTC, and the smallest for bulk density (BD), pH, and V. The minimum number of soil subsamples to form a compound and representative sample varied between 1 (pH and V) and 241 (Mg), with a mean of 64 subsamples. In relation to spatial dependence, P and V presented, respectively, strong and weak dependence, while the other attributes displayed a moderate dependency. Thus, the range of physical characteristics varied from 2.56 to 4.32 m and from 1.82 to 5.64 m for chemical characteristics.

A low-cost method for carbon nanotubes (CNTs) network production from solutions on flexible polyethylene naphthalate substrates has been adopted to prepare high quality and well characterized SWCNT bundle layers to be used as the active layer in chemiresistor gas sensors. Two types of SWCNTs have been tested: pristine SWCNTs, deposited from a surfactant solution, and covalently functionalized SWCNTs, deposited from a dimethyl-acetamide solution. The humidity effects on the sensitivity of the SWCNTs network to NH3 have been investigated. The results show that relative humidity favors the response to NH3, confirming recent theoretical predictions. The COOH-functionalized sample displays the largest response owing to both its hydrophilic nature, favoring the interaction with H2O molecules, and its largest surface area. Compared to data available in the literature, the present sensors display a remarkable sensitivity well below the ppm range, which makes them quite promising for environmental and medical applications, where NH3 concentrations (mostly of the order of tens of ppb) have to be detected. [ABSTRACT FROM AUTHOR]

Metabolic plasticity is a hallmark of cancer, and metabolic alterations represent a promising therapeutic target. Since cellular metabolism is controlled by membrane traffic at multiple levels, we investigated the involvement of TBC1 domain-containing proteins (TBC1Ds) in the regulation of cancer metabolism. These proteins are characterized by the presence of a RAB-GAP domain, the TBC1 domain, and typically function as attenuators of RABs, the master switches of membrane traffic. However, a number of TBC1Ds harbor mutations in their catalytic residues, predicting biological functions different from direct regulation of RAB activities. Herein, we report that several genes encoding for TBC1Ds are expressed at higher levels in triple-negative breast cancers (TNBC) vs. other subtypes of breast cancers (BC), and predict prognosis. Orthogonal transcriptomics/metabolomics analysis revealed that the expression of prognostic TBC1Ds correlates with elevated glycolytic metabolism in BC cell lines. In-depth investigations of the three top hits from the previous analyses (TBC1D31, TBC1D22B and TBC1D7) revealed that their elevated expression is causal in determining a glycolytic phenotype in TNBC cell lines. We further showed that the impact of TBC1D7 on glycolytic metabolism of BC cells is independent of its known participation in the TSC1/TSC2 complex and consequent downregulation of mTORC1 activity. Since TBC1D7 behaves as an independent prognostic biomarker in TNBC, it could be used to distinguish good prognosis patients who could be spared aggressive therapy from those with a poor prognosis who might benefit from anti-glycolytic targeted therapies. Together, our results highlight how TBC1Ds connect disease aggressiveness with metabolic alterations in TNBC. Given the high level of heterogeneity among this BC subtype, TBC1Ds could represent important tools in predicting prognosis and guiding therapy decision-making., (© 2024. The Author(s).)

One open question in the biology of growth factor receptors is how a quantitative input (i.e., ligand concentration) is decoded by the cell to produce specific response(s). Here, we show that an EGFR endocytic mechanism, non-clathrin endocytosis (NCE), which is activated only at high ligand concentrations and targets receptor to degradation, requires a tripartite organelle platform involving the plasma membrane (PM), endoplasmic reticulum (ER) and mitochondria. At these contact sites, EGFR-dependent, ER-generated Ca 2+ oscillations are sensed by mitochondria, leading to increased metabolism and ATP production. Locally released ATP is required for cortical actin remodeling and EGFR-NCE vesicle fission. The same biochemical circuitry is also needed for an effector function of EGFR, i.e., collective motility. The multiorganelle signaling platform herein described mediates direct communication between EGFR signaling and mitochondrial metabolism, and is predicted to have a broad impact on cell physiology as it is activated by another growth factor receptor, HGFR/MET., (© 2024. The Author(s).)

Discerning the impact of the coherent motion of the nuclei on the timing and efficiency of charge transfer at the donor-acceptor interface is essential for designing performance-enhanced optoelectronic devices. Here, we employ an experimental approach using photocurrent detection in coherent multidimensional spectroscopy to excite a donor aromatic macrocycle and collect the charge transferred to a 2D acceptor layer. For this purpose, we prepared a cobalt phthalocyanine-graphene (CoPc-Gr) interface. Unlike blends, the well-ordered architecture achieved through the physical separation of the two layers allows us to unambiguously collect the electrical signal from graphene alone and associate it with a microscopic understanding of the whole process. The CoPc-Gr interface exhibits an ultrafast electron-transfer signal, stemming from an interlayer mechanism. Remarkably, the signal presents an oscillating time evolution modulated by coherent vibrations originating from the laser-excited CoPc states. By performing Fourier analysis on the beatings and correlating it with the Raman features, along with a comprehensive first-principles characterization of the vibrational coupling in the CoPc excited states, we successfully identify both the orbitals and molecular vibrations that promote the charge transfer at the interface.

Integrons are genetic platforms that capture, rearrange and express mobile modules called gene cassettes. The best characterized gene cassettes encode antibiotic resistance, but the function of most integron gene cassettes remains unknown. Functional predictions suggest that many gene cassettes could encode proteins that facilitate interactions with other cells and with the extracellular environment. Because cell interactions are essential for biofilm stability, we sequenced gene cassettes from biofilms growing on the surface of the marine macroalgae Ulva australis and Sargassum linearifolium . Algal samples were obtained from coastal rock platforms around Sydney, Australia, using seawater as a control. We demonstrated that integrons in microbial biofilms did not sample genes randomly from the surrounding seawater, but harboured specific functions that potentially provided an adaptive advantage to both the bacterial cells in biofilm communities and their macroalgal host. Further, integron gene cassettes had a well-defined spatial distribution, suggesting that each bacterial biofilm acquired these genetic elements via sampling from a large but localized pool of gene cassettes. These findings suggest two forms of filtering: a selective acquisition of different integron-containing bacterial species into the distinct biofilms on Ulva and Sargassum surfaces, and a selective retention of unique populations of gene cassettes at each sampling location.

With the emergence of novel sensing materials and the increasing opportunities to address safety and life quality priorities of our society, gas sensing is experiencing an outstanding growth. Among the characteristics required to assess performances, the overall speed of response and recovery is adding to the well-established stability, selectivity, and sensitivity features. In this review, we focus on fast detection with chemiresistor gas sensors, focusing on both response time and recovery time that characterize their dynamical response. We consider three classes of sensing materials operating in a chemiresistor architecture, exposed to the most investigated pollutants, such as NH3, NO2, H2S, H2, ethanol, and acetone. Among sensing materials, we first selected nanostructured metal oxides, which are by far the most used chemiresistors and can provide a solid ground for performance improvement. Then, we selected nanostructured carbon sensing layers (carbon nanotubes, graphene, and reduced graphene), which represent a promising class of materials that can operate at room temperature and offer many possibilities to increase their sensitivities via functionalization, decoration, or blending with other nanostructured materials. Finally, transition metal dichalcogenides are presented as an emerging class of chemiresistive layers that bring what has been learned from graphene into a quite large portfolio of chemo-sensing platforms. For each class, studies since 2019 reporting on chemiresistors that display less than 10 s either in the response or in the recovery time are listed. We show that for many sensing layers, the sum of both response and recovery times is already below 10 s, making them promising devices for fast measurements to detect, e.g., sudden bursts of dangerous emissions in the environment, or to track the integrity of packaging during food processing on conveyor belts at pace with industrial production timescales.

Boosted by the emerging need for highly integrated gas sensors in the internet of things (IoT) ecosystems, electronic noses (e-noses) are gaining interest for the detection of specific molecules over a background of interfering gases. The sensing of nitrogen dioxide is particularly relevant for applications in environmental monitoring and precision medicine. Here we present an easy and efficient functionalization procedure to covalently modify graphene layers, taking advantage of diazonium chemistry. Separate graphene layers were functionalized with one of three different aryl rings: 4-nitrophenyl, 4-carboxyphenyl and 4-bromophenyl. The distinct modified graphene layers were assembled with a pristine layer into an e-nose for NO 2 discrimination. A remarkable sensitivity to NO 2 was demonstrated through exposure to gaseous solutions with NO 2 concentrations in the 1-10 ppm range at room temperature. Then, the discrimination capability of the sensor array was tested by carrying out exposure to several interfering gases and analyzing the data through multivariate statistical analysis. This analysis showed that the e-nose can discriminate NO 2 among all the interfering gases in a two-dimensional principal component analysis space. Finally, the e-nose was trained to accurately recognize NO 2 contributions with a linear discriminant analysis approach, thus providing a metric for discrimination assessment with a prediction accuracy above 95 %., (© 2023 Wiley-VCH GmbH.)

The p140Cap adaptor protein is a tumor suppressor in breast cancer associated with a favorable prognosis. Here we highlight a function of p140Cap in orchestrating local and systemic tumor-extrinsic events that eventually result in inhibition of the polymorphonuclear myeloid-derived suppressor cell function in creating an immunosuppressive tumor-promoting environment in the primary tumor, and premetastatic niches at distant sites. Integrative transcriptomic and preclinical studies unravel that p140Cap controls an epistatic axis where, through the upstream inhibition of β-Catenin, it restricts tumorigenicity and self-renewal of tumor-initiating cells limiting the release of the inflammatory cytokine G-CSF, required for polymorphonuclear myeloid-derived suppressor cells to exert their local and systemic tumor conducive function. Mechanistically, p140Cap inhibition of β-Catenin depends on its ability to localize in and stabilize the β-Catenin destruction complex, promoting enhanced β-Catenin inactivation. Clinical studies in women show that low p140Cap expression correlates with reduced presence of tumor-infiltrating lymphocytes and more aggressive tumor types in a large cohort of real-life female breast cancer patients, highlighting the potential of p140Cap as a biomarker for therapeutic intervention targeting the β-Catenin/ Tumor-initiating cells /G-CSF/ polymorphonuclear myeloid-derived suppressor cell axis to restore an efficient anti-tumor immune response., (© 2023. The Author(s).)

Sensor arrays are currently attracting the interest of researchers due to their potential of overcoming the limitations of single sensors regarding selectivity, required by specific applications. Among the materials used to develop sensor arrays, graphene has not been so far extensively exploited, despite its remarkable sensing capability. Here we present the development of a graphene-based sensor array prepared by dropcasting nanostructure and nanocomposite graphene solution on interdigitated substrates, with the aim to investigate the capability of the array to discriminate several gases related to specific applications, including environmental monitoring, food quality tracking, and breathomics. This goal is achieved in two steps: at first the sensing properties of the array have been assessed through ammonia exposures, drawing the calibration curves, estimating the limit of detection, which has been found in the ppb range for all sensors, and investigating stability and sensitivity; then, after performing exposures to acetone, ethanol, 2-propanol, sodium hypochlorite, and water vapour, chemometric tools have been exploited to investigate the discrimination capability of the array, including principal component analysis (PCA), linear discriminant analysis (LDA), and Mahalanobis distance. PCA shows that the array was able to discriminate all the tested gases with an explained variance around 95%, while with an LDA approach the array can be trained to accurately recognize unknown gas contribution, with an accuracy higher than 94%.

Electronic noses (e-noses) have received considerable interest in the past decade as they can match the emerging needs of modern society such as environmental monitoring, health screening, and food quality tracking. For practical applications of e-noses, it is necessary to collect large amounts of data from an array of sensing devices that can detect interactions with molecules reliably and analyze them via pattern recognition. The use of graphene (Gr)-based arrays of chemiresistors in e-noses is still virtually missing, though recent reports on Gr-based chemiresistors have disclosed high sensing performances upon functionalization of the pristine layer, opening up the possibility of being implemented into e-noses. In this work, with the aim of creating a robust and chemically stable interface that combines the chemical properties of metal phthalocyanines (M-Pc, M = Fe, Co, Ni, Zn) with the superior transport properties of Gr, an array of Gr-based chemiresistor sensors functionalized with drop-cast M-Pc thin layers has been developed. The sensing capability of the array was tested towards biomarkers for breathomics application, with a focus on ammonia (NH 3 ). Exposure to NH 3 has been carried out drawing the calibration curve and estimating the detection limit for all the sensors. The discrimination capability of the array has then been tested, carrying out exposure to several gases (hydrogen sulfide, acetone, ethanol, 2-propanol, water vapour and benzene) and analysing the data through principal component analysis (PCA). The PCA pattern recognition results show that the developed e-nose is able to discriminate all the tested gases through the synergic contribution of all sensors., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Asymmetric cell division is a key tumor suppressor mechanism that prevents the uncontrolled expansion of the stem cell (SC) compartment by generating daughter cells with alternative fates: one retains SC identity and enters quiescence and the other becomes a rapidly proliferating and differentiating progenitor. A critical player in this process is Numb, which partitions asymmetrically at SC mitosis and inflicts different proliferative and differentiative fates in the two daughters. Here, we show that asymmetric Numb partitioning per se is insufficient for the proper control of mammary SC dynamics, with differential phosphorylation and functional inactivation of Numb in the two progeny also required. The asymmetric phosphorylation/inactivation of Numb in the progenitor is mediated by the atypical PKCζ isoform. This mechanism is subverted in breast cancer via aberrant activation of PKCs that phosphorylate Numb in both progenies, leading to symmetric division and expansion of the cancer SC compartment, associated with aggressive disease. Thus, Numb phosphorylation represents a target for breast cancer therapy., (© 2022 Filippone et al.)

With the aim to identify charge transfer channels underlying device development and operation, X-Ray Photoelectron Spectroscopy (XPS), Near-Edge X-Ray Absorption Fine Structure (NEXAFS), and Resonant Photoelectron Spectroscopy (ResPES) have been employed to characterize a novel heterointerface obtained by the controlled evaporation of a Nickel Phthalocyanine (NiPc) monolayer on a single layer of Graphene (Gr) on SiC substrate. Indeed, the Gr-NiPc interface could be a promising candidate for different applications in the field of photonics, optoelectronics, and sensing, provided that clear information on the charge transfer mechanisms at the Gr-NiPc interface can be obtained. The analysis of the spectroscopic data has shown the effective functionalization and the horizontally-flat disposition of the NiPc complexes over the Gr layer. With this geometry, the main intermolecular interaction experienced by the NiPc species is the coupling with the Gr substrate, through π-symmetry orbitals, as revealed by the different behaviour of the valence band photoemission at resonance with the N K-edge and Ni L 3 -edge. These results have been supported by the analysis of density functional theory (DFT) calculations, that allowed for a rationalization of the experimental data, showing that charge transfer at the interface occurs from the doubly degenerate e g LUMO orbital, involving mainly N and C (pyrrole ring) p z states, to the holes in the p-doped graphene layer.

The remarkable potential of breath analysis in medical care and diagnosis, and the consequent development of electronic noses, is currently attracting the interest of the research community. This is mainly due to the possibility of applying the technique for early diagnosis, screening campaigns, or tracking the effectiveness of treatment. Carbon nanotubes (CNTs) are known to be good candidates for gas sensing, and they have been recently considered for the development of electronic noses. The present work has the aim of reviewing the available literature on the development of CNTs-based electronic noses for breath analysis applications, detailing the functionalization procedure used to prepare the sensors, the breath sampling techniques, the statistical analysis methods, the diseases under investigation, and the population studied. The review is divided in two main sections: one focusing on the e-noses completely based on CNTs and one reporting on the e-noses that feature sensors based on CNTs, along with sensors based on other materials. Finally, a classification is presented among studies that report on the e-nose capability to discriminate biomarkers, simulated breath, and animal or human breath., Competing Interests: The authors declare no conflicts of interest.

An easy and cost-effective method is presented to functionalize graphene through thermally activated dimerization of 2,5-diaryltetrazoles. Consistently with the experimental spectroscopic results, theoretical calculations demonstrate that during the thermal treatment a dimerization process to tetrazine is energetically more favorable than covalent grafting. Since both the functionalization method by thermal activation and the use of tetrazoles have never been considered before to prepare graphene-based chemiresistors, this represents a promising approach to develop graphene-related sensing platforms. Five different 2,5-diaryltetrazoles have been tested here for the effective functionalization of low-defect graphene layers on silicon nitride. Based on these layers, an array of sensors has been prepared for testing upon ammonia exposure. The tests on the sensing performances clearly show sensitivity to ammonia, extending the current range of ammonia detection with a graphene-based chemiresistor down to the sub-ppm range, as results from a benchmarking with data available in the literature. Furthermore, all sensors perform better than bare graphene. Density functional theory (DFT) calculations, carried out on a model of the best performing layer of the array, provided the theoretical framework to rationalize the sensing mechanism and disclose a dual role played by the tetrazine molecules, (i) acting as ammonia concentrators and (ii) mediating the electron transfer between ammonia and graphene.

Gas sensors are essential in several fields and, in general, features such as high sensitivity, quick response, and fast recovery are required, along with low power consumption and low cost. Graphene is considered a promising material for gas sensing applications, its functionalization often being a requisite. In the present study, we developed competitive and promising gas sensors for ammonia detection. Interestingly, we present an easy and efficient method to functionalize graphene by using diazonium chemistry with different functional groups. Moreover, we prove the superior sensing capability of our covalently modified graphene layers. These experimental data have been consistently interpreted by theoretical calculations, which reveal a defect-driven sensor's response to ammonia. These results open the possibility of a comprehensive design and use of these graphene-based sensors in real applications., (© 2022 Wiley-VCH GmbH.)

Objective: Molecular tests predicting the risk of distant recurrence (DR) can be used to assist therapy decision-making in oestrogen receptor-positive (ER+) and human epidermal growth factor receptor 2-negative (HER2-) breast cancer patients after considerations of standard clinical markers. The Oncotype DX Recurrence Score (RS) is a widespread tool used for this purpose. Here, we compared the RS with the StemPrintER Risk Score (SPRS), a novel genomic predictor with a unique biological basis in its ability to measure the expression of cancer stemness genes., Materials and Methods: We benchmarked the SPRS vs. RS, alone or in combination with clinicopathological variables expressed by the Clinical Treatment Score (CTS), for the prognostication of DR in a retrospective cohort of 776 postmenopausal patients with ER+/HER2-breast cancer enrolled in the translational arm of the randomised Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial. Likelihood ratio (LR) with χ 2 test and C-index were used to assess prognostic performance for the entire ten-year follow-up period and in early (0-5 years) and late (5-10 years) intervals., Results: In all patients, the SPRS provided significantly more prognostic information than the RS for ten-year DR prognostication (C-index = 0.688, LR-χ 2  = 33.4 vs. C-index = 0.641, LR-χ 2  = 22.1) and for late (5-10 years) DR prognostication (C-index = 0.689, LR-χ 2  = 18.8 vs. C-index = 0.571, LR-χ 2  = 4.7). The SPRS also provided more prognostic information than the RS when added to the CTS in all patients (CTS + SPRS: LR-Δχ 2  = 14.9; CTS + RS: LR-Δχ 2  = 9.7) and in node-negative patients (CTS + SPRS: LR-Δχ 2  = 11.7; CTS + RS: LR-Δχ 2  = 6.6)., Conclusions: In postmenopausal ER+/HER2- breast cancer patients, SPRS provided more prognostic information than RS for DR when used alone or in combination with the CTS. The SPRS could therefore potentially identify high-risk patients, who might benefit from aggressive treatments, from low-risk patients who might safely avoid adjuvant chemotherapy or prolongation of endocrine therapy., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Pece and Di Fiore report a patent EP/20.06.16/EPA16175354 and a patent EP/20173612.1, both pending to Tiziana Life Sciences (TLS). They also report a research sponsored grant from TLS from June 2014 to June 2018 related to the development of StemPrintER, outside the submitted work which was completely developed with academic funding. Sestak reports personal fees from Myriad Genetics and Pfizer Oncology, outside the submitted work. Viale reports personal fees from Roche Genentech, Daiichi-Sankyo, AstraZeneca, Agilent, Menarini and Ventana, outside the submitted work. Dowsett reports personal fees from Radius, Myriad, Orion, G1, AbbVie, H3 Biomedicine, Lilly, Zentalis, Agilent and Nanostring, outside the submitted work. All other authors declare no other competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Cancer stem cells (CSC) have been implicated in tumor progression. In ovarian carcinoma (OC), CSC drive tumor formation, dissemination and recurrence, as well as drug resistance, thus contributing to the high death-to-incidence ratio of this disease. However, the molecular basis of such a pathogenic role of ovarian CSC (OCSC) has been elucidated only to a limited extent. In this context, the functional contribution of the L1 cell adhesion molecule (L1CAM) to OC stemness remains elusive., Methods: The expression of L1CAM was investigated in patient-derived OCSC. The genetic manipulation of L1CAM in OC cells provided gain and loss-of-function models that were then employed in cell biological assays as well as in vivo tumorigenesis experiments to assess the role of L1CAM in OC cell stemness and in OCSC-driven tumor initiation. We applied antibody-mediated neutralization to investigate L1CAM druggability. Biochemical approaches were then combined with functional in vitro assays to study the molecular mechanisms underlying the functional role of L1CAM in OCSC., Results: We report that L1CAM is upregulated in patient-derived OCSC. Functional studies showed that L1CAM promotes several stemness-related properties in OC cells, including sphere formation, tumor initiation and chemoresistance. These activities were repressed by an L1CAM-neutralizing antibody, pointing to L1CAM as a druggable target. Mechanistically, L1CAM interacted with and activated fibroblast growth factor receptor-1 (FGFR1), which in turn induced the SRC-mediated activation of STAT3. The inhibition of STAT3 prevented L1CAM-dependent OC stemness and tumor initiation., Conclusions: Our study implicate L1CAM in the tumorigenic function of OCSC and point to the L1CAM/FGFR1/SRC/STAT3 signaling pathway as a novel driver of OC stemness. We also provide evidence that targeting this pathway can contribute to OC eradication., (© 2021. The Author(s).)

An array of carbon nanotube (CNT)-based sensors was produced for sensing selective biomarkers and evaluating breathomics applications with the aid of clustering and classification algorithms. We assessed the sensor array performance in identifying target volatiles and we explored the combination of various classification algorithms to analyse the results obtained from a limited dataset of exhaled breath samples. The sensor array was exposed to ammonia (NH 3 ), nitrogen dioxide (NO 2 ), hydrogen sulphide (H 2 S), and benzene (C 6 H 6 ). Among them, ammonia (NH 3 ) and nitrogen dioxide (NO 2 ) are known biomarkers of chronic obstructive pulmonary disease (COPD). Calibration curves for individual sensors in the array were obtained following exposure to the four target molecules. A remarkable response to ammonia (NH 3 ) and nitrogen dioxide (NO 2 ), according to benchmarking with available data in the literature, was observed. Sensor array responses were analyzed through principal component analysis (PCA), thus assessing the array selectivity and its capability to discriminate the four different target volatile molecules. The sensor array was then exposed to exhaled breath samples from patients affected by COPD and healthy control volunteers. A combination of PCA, supported vector machine (SVM), and linear discrimination analysis (LDA) shows that the sensor array can be trained to accurately discriminate healthy from COPD subjects, in spite of the limited dataset., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Although ectopic overexpression of miRNAs can influence mammary normal and cancer stem cells (SCs/CSCs), their physiological relevance remains uncertain. Here, we show that miR-146 is relevant for SC/CSC activity. MiR-146a/b expression is high in SCs/CSCs from human/mouse primary mammary tissues, correlates with the basal-like breast cancer subtype, which typically has a high CSC content, and specifically distinguishes cells with SC/CSC identity. Loss of miR-146 reduces SC/CSC self-renewal in vitro and compromises patient-derived xenograft tumor growth in vivo, decreasing the number of tumor-initiating cells, thus supporting its pro-oncogenic function. Transcriptional analysis in mammary SC-like cells revealed that miR-146 has pleiotropic effects, reducing adaptive response mechanisms and activating the exit from quiescent state, through a complex network of finely regulated miRNA targets related to quiescence, transcription, and one-carbon pool metabolism. Consistent with these findings, SCs/CSCs display innate resistance to anti-folate chemotherapies either in vitro or in vivo that can be reversed by miR-146 depletion, unmasking a "hidden vulnerability" exploitable for the development of anti-CSC therapies., (© 2021 Tordonato et al.)

The posttranslational regulation of transferrin receptor (TfR1) is largely unknown. We investigated whether iron availability affects TfR1 endocytic cycle and protein stability in HepG2 hepatoma cells exposed to ferric ammonium citrate (FAC). NH 4 Cl and bafilomycin A1, but not the proteasomal inhibitor MG132, prevented the FAC-mediated decrease in TfR1 protein levels, thus indicating lysosomal involvement. Knockdown experiments showed that TfR1 lysosomal degradation is independent of 1) endocytosis mediated by the clathrin adaptor AP2; 2) Tf, which was suggested to facilitate TfR1 internalization; 3) H-ferritin; and 4) MARCH8, previously implicated in TfR1 degradation. Notably, FAC decreased the number of TfR1 molecules at the cell surface and increased the Tf endocytic rate. Colocalization experiments confirmed that, upon FAC treatment, TfR1 was endocytosed in an AP2- and Tf-independent pathway and trafficked to the lysosome for degradation. This unconventional endocytic regulatory mechanism aimed at reducing surface TfR1 may represent an additional posttranslational control to prevent iron overload. Our results show that iron is a key regulator of the trafficking of TfR1, which has been widely used to study endocytosis, often not considering its function in iron homeostasis.

Photovoltaic (PV) cells based on single-walled carbon nanotube (SWCNT)/silicon (Si) and multiwalled carbon nanotube (MWCNT)/Si junctions were tested under exposure to NH 3 in the 0-21 ppm concentration range. The PV cell parameters remarkably changed upon NH 3 exposure, suggesting that these junctions, while being operated as PV cells, can react to changes in the environment, thereby acting as NH 3 gas sensors. Indeed, by choosing the open-circuit voltage, V OC , parameter as read-out, it was found that these cells behaved as gas sensors, operating at room temperature with a response higher than chemiresistors developed on the same layers. The sensitivity was further increased when the whole current-voltage (I-V) curve was collected and the maximum power values were tracked upon NH 3 exposure.