Overview of Gas Sensors Focusing on Chemoresistive Ones for Cancer Detection

The necessity of detecting and recognizing gases is crucial in many research and application fields, boosting, in the last years, their continuously evolving technology. The basic detection principle of gas sensors relies on the conversion of gas concentration changes into a readable signal that can be analyzed to calibrate sensors to detect specific gases or mixtures. The large variety of gas sensor types is here examined in detail, along with an accurate description of their fundamental characteristics and functioning principles, classified based on their working mechanisms (electrochemical, resonant, optical, chemoresistive, capacitive, and catalytic). This review is particularly focused on chemoresistive sensors, whose electrical resistance changes because of chemical reactions between the gas and the sensor surface, and, in particular, we focus on the ones developed by us and their applications in the medical field as an example of the technological transfer of this technology to medicine. Nowadays, chemoresistive sensors are, in fact, strong candidates for the implementation of devices for the screening and monitoring of tumors (the second worldwide cause of death, with ~9 million deaths) and other pathologies, with promising future perspectives that are briefly discussed as well

Reproducibility and Repeatability Tests on (SnTiNb)O2 Sensors in Detecting ppm-Concentrations of CO and Up to 40% of Humidity: A Statistical Approach

: Nowadays, most medical-diagnostic, environmental monitoring, etc. devices employ sensors whose fabrication reproducibility and response repeatability assessment are crucial. The former consists of large-scale sensor manufacture through a standardized process with almost identical morphology and behavior, while the latter consists of giving the same response upon repeating the same stimulus. The thermo-activated chemoresistive sensors, which change their conductance by interacting with the molecules composing the surrounding gas, are currently employed in many devices: in particular, thick-film (SnTiNb)O2 nanosensors were demonstrated to be particularly suitable in the medical and biological fields. Therefore, a set of thirteen of them, randomly selected from the same screen-printing deposition, were laboratory tested, and the outcomes were statistically analyzed in order to assess their consistency. At first, the working temperature that maximized both the sensor sensitivity and response repeatability was identified. Then, the sensors were subjected to different gas concentrations and humidities at this optimal working temperature. It resulted in the (SnTiNb)O2 nanosensors detecting and discriminating CO concentrations as low as 1 ppm and at high humidity degrees (up to 40%) with high repeatability since the response relative standard error ranged from 0.8 to 3.3% for CO and from 3.6 to 5.4% for water vapor

Chemoresistive Nanosensors Employed to Detect Blood Tumor Markers in Patients Affected by Colorectal Cancer in a One-Year Follow Up

Simple Summary Since colorectal cancer represents one of the most diffused pathologies worldwide, usually lacking specific symptoms, it is crucial to develop and validate innovative low-invasive techniques to detect it. Here, a device based on an array of nanostructured gas sensors has been employed to analyze and discriminate the exhalations of blood samples collected from colorectal cancer-affected patients at different stages of their pre- and post-surgery therapeutic path. The device was clearly able to distinguish between the pre-surgery samples, where the tumor was present, and the one-year post-surgery ones, following the tumor removal. These results raise high hopes for the device's clinical validation and its future use in clinical follow-up protocols, patient health status monitoring, and to detect possible post-treatment relapses. Colorectal cancer (CRC) represents 10% of the annual tumor diagnosis and deaths occurring worldwide. Given the lack of specific symptoms, which could determine a late diagnosis, the research for specific CRC biomarkers and for innovative low-invasive methods to detect them is crucial. Therefore, on the basis of previously published results, some volatile organic compounds (VOCs), detectable through gas sensors, resulted in particularly promising CRC biomarkers, making these sensors suitable candidates to be employed in CRC screening devices. A new device was employed here to analyze the exhalations of blood samples collected from CRC-affected patients at different stages of their pre- and post-surgery therapeutic path, in order to assess the sensor's capability for discriminating among these samples. The stages considered were: the same day of the surgical treatment (T1); before the hospital discharge (T2); after one month and after 10-12 months from surgery (T3 and T4, respectively). This device, equipped with four different sensors based on different metal-oxide mixtures, enabled a distinction between T1 and T4 with a sensitivity and specificity of 93% and 82%, respectively, making it suitable for clinical follow-up protocols, patient health status monitoring and to detect possible post-treatment relapses

Molecular Signature of Biological Aggressiveness in Clear Cell Sarcoma of the Kidney (CCSK)

: Clear cell sarcoma of the kidney (CCSK) is a rare pediatric renal tumor with a worse prognosis than Wilms' tumor. Although recently, BCOR internal tandem duplication (ITD) has been found as a driver mutation in more than 80% of cases, a deep molecular characterization of this tumor is still lacking, as well as its correlation with the clinical course. The aim of this study was to investigate the differential molecular signature between metastatic and localized BCOR-ITD-positive CCSK at diagnosis. Whole-exome sequencing (WES) and whole-transcriptome sequencing (WTS) were performed on six localized and three metastatic BCOR-ITD-positive CCSKs, confirming that this tumor carries a low mutational burden. No significant recurrences of somatic or germline mutations other than BCOR-ITD were identified among the evaluated samples. Supervised analysis of gene expression data showed enrichment of hundreds of genes, with a significant overrepresentation of the MAPK signaling pathway in metastatic cases (p < 0.0001). Within the molecular signature of metastatic CCSK, five genes were highly and significantly over-expressed: FGF3, VEGFA, SPP1, ADM, and JUND. The role of FGF3 in the acquisition of a more aggressive phenotype was investigated in a cell model system obtained by introducing the ITD into the last exon of BCOR by Crispr/Cas9 gene editing of the HEK-293 cell line. Treatment with FGF3 of BCOR-ITD HEK-293 cell line induced a significant increase in cell migration versus both untreated and scramble cell clone. The identification of over-expressed genes in metastatic CCSKs, with a particular focus on FGF3, could offer new prognostic and therapeutic targets in more aggressive cases

The efficacy of imatinib mesylate in patients with FIP1L1-PDGFRα-positive hypereosinophilic syndrome. Results of a multicenter prospective study

BACKGROUND AND OBJECTIVES: The hypereosinophilic syndrome (HES) may be associated with the fusion of the platelet derived growth factor receptor a (PDGFRalpha) gene with the FIP1L1 gene in chromosome 4 coding for a constitutively activated PDGFRalpha tyrosine kinase. These cases with FIP1L1-PDGFRalpha rearrangement have been reported to be very sensitive to the tyrosine kinase inhibitor imatinib mesylate. DESIGN AND METHODS: A prospective multicenter study of idiopathic or primary HES was established in 2001 (Study Protocol Registration no. NCT 0027 6929). One hundred and ninety-six patients were screened, of whom 72 where identified as having idiopathic or primary HES and 63 were treated with imatinib 100 to 400 mg daily. RESULTS: Twenty-seven male patients carried the FIP1L1-PDGFRalpha rearrangement. All 27 achieved a complete hematologic remission (CHR) and became negative for the fusion transcripts according to reverse transcriptase polymerase chain reaction (RT-PCR) analysis. With a median follow-up of 25 months (15-60 months) all 27 patients remain in CHR and RT-PCR negative, and continue treatment at a dose of 100 to 400 mg daily. In three patients imatinib treatment was discontinued for few months, the fusion transcript became rapidly detectable, and then again undetectable upon treatment reassumption. Thirty-six patients did not carry the rearrangement; of these, five (14%) achieved a CHR, which was lost in all cases after 1 to 15 months. INTERPRETATION AND CONCLUSIONS: All patients meeting the criteria for idiopathic or primary HES should be screened for the FIP1L1-PDGFRalpha rearrangement. For all patients with this rearrangement, chronic imatinib treatment at doses as low as 100 mg daily ensures complete and durable responses

CD133 Positive Embryonal Rhabdomyosarcoma Stem-Like Cell Population Is Enriched in Rhabdospheres

Cancer stem cells (CSCs) have been identified in a number of solid tumors, but not yet in rhabdomyosarcoma (RMS), the most frequently occurring soft tissue tumor in childhood. Hence, the aim of this study was to identify and characterize a CSC population in RMS using a functional approach. We found that embryonal rhabdomyosarcoma (eRMS) cell lines can form rhabdomyosarcoma spheres (short rhabdospheres) in stem cell medium containing defined growth factors over several passages. Using an orthotopic xenograft model, we demonstrate that a 100 fold less sphere cells result in faster tumor growth compared to the adherent population suggesting that CSCs were enriched in the sphere population. Furthermore, stem cell genes such as oct4, nanog, c-myc, pax3 and sox2 are significantly upregulated in rhabdospheres which can be differentiated into multiple lineages such as adipocytes, myocytes and neuronal cells. Surprisingly, gene expression profiles indicate that rhabdospheres show more similarities with neuronal than with hematopoietic or mesenchymal stem cells. Analysis of these profiles identified the known CSC marker CD133 as one of the genes upregulated in rhabdospheres, both on RNA and protein levels. CD133+ sorted cells were subsequently shown to be more tumorigenic and more resistant to commonly used chemotherapeutics. Using a tissue microarray (TMA) of eRMS patients, we found that high expression of CD133 correlates with poor overall survival. Hence, CD133 could be a prognostic marker for eRMS. These experiments indicate that a CD133+ CSC population can be enriched from eRMS which might help to develop novel targeted therapies against this pediatric tumor

Use of Nanostructured Chemoresistive Sensors to Detect Tumor Cells, Analyzing Blood and Biopsy Samples and Development of a More Sophisticated Electronic Device for Sensors

Il tumore al colon-retto è, ad oggi, un grave problema di salute pubblica, in quanto costituisce il 10% di tutti i tumori annualmente diagnosticati e dei decessi strettamente correlati a questo tipo di patologia in tutto il mondo. Per questo motivo, il riconoscimento e monitoraggio dei marcatori tumorali per mezzo di tecniche completamente non invasive e affidabili, rappresenta un obiettivo di ricerca fortemente condiviso dalla comunità scientifica mondiale. ll riconoscimento univoco di questi marcatori rappresenta quindi un aspetto di cruciale importanza nello screening tumorale, che permetterebbe il miglioramento dell’affidabilità dei protocolli di screening attualmente in uso e, l’eventuale individuazione della malattia in stato precoce, aumentando così i margini di intervento e le probabilità di guarigione. Questa tesi rappresenta un lavoro di durata triennale, atto all’individuazione di marker tumorali volatili (VOC) emanati dal metabolismo cellulare alterato dal cancro al colon-retto (CCR), per mezzo di sensori chemoresistivi nanostrutturati a film spesso. A questo fine, sono state analizzate diverse tipologie di campioni biologici come feci, sangue, tessuti bioptici e cellule immortalizzate, tramite un dispositivo innovativo brevettato (Italia n° 102015000057717), nominato SCENT B1, che ospita un array di quattro sensori del suddetto tipo, basati su materiali sensibili diversi (combinazioni di ossidi di stagno, titanio, tungsteno, niobio, vanadio e tantalio). La scelta dei sensori per l’applicazione in campo biomedicale è stata effettuata sulla base di test di laboratorio (presso il Laboratorio Sensori, Dipartimento di Fisica, Università di Ferrara) che hanno messo in luce la loro idoneità nell’individuare i composti organici volatili di interesse con il miglior compromesso fra sensibilità e specificità. I risultati ottenuti nel corso dello studio sono stati piuttosto incoraggianti, in quanto mettono in luce la capacità dei sensori scelti di distinguere le feci, i tessuti e il sangue prelevati da soggetti affetti da cancro al colon-retto da quelli prelevati da soggetti sani (giovani e senza fattori di rischio rilevanti), inseriti nello studio come controparti di controllo (paragrafi 4.1 – 4.6). I test svolti sulle cellule immortalizzate hanno messo in luce la sensibilità dei sensori in relazione alla tipologia di cellule analizzate, alla loro concentrazione iniziale di piastratura e, alle ore di incubazione a cui sono state sottoposte (24, 48,72 ore). E’ stato inoltre presentato il progetto di rinnovamento del dispositivo SCENT, partendo dalla riprogettazione dell’involucro (con conseguente riarrangiamento degli spazi interni), alla riprogettazione dell’apparato elettronico e software. Quest’ultimo è stato riadattato, sfruttando componenti elettroniche di ultima generazione che esibiscono rumori elettronici trascurabili, portando a eccellenti rapporti di segnale-rumore, e ad un basso surriscaldamento di tutto l’apparato. Infine, è stato avviato un nuovo studio al termine del 2020, con lo scopo di eseguire un protocollo di follow-up nei pazienti oncologici tramite quattro prelievi di sangue effettuati in quattro momenti diversi del percorso post-operatorio. Questo processo ha lo scopo di eseguire un monitoraggio dinamico del paziente in seguito all’intervento chirurgico, rivelando così un’eventuale insorgenza di recidive e/o complicazioni.Colorectal cancer (CRC) is, nowadays, a severe problem of public health, counting the 10% of all the tumors annually diagnosed worldwide and of their strictly related deaths. On this basis, the non-invasive tumoral markers recognition and monitoring represent a strongly shared research topic in the whole world scientific community. The detection of these markers represents a crucial aspect in field of tumor prevention, allowing to improve the current screening protocols. The establishment of a reliable and accurate novel screening protocol might promote the early-stage tumor detection, enhancing the healing probability. This thesis reports a three-year work, aimed to reveal the volatile tumor-markers (VOCs) exhaled by CRC-affected cells (mainly produced by their membrane peroxidation and altered metabolism), by means of thick-film nanostructured chemoresistive metal-oxide sensors. With this aim, a wide range of diverse biological samples have been investigated, such as feces, blood, tumor tissues, and immortalized cells, by using the innovative patented devices: SCENT B1 (Italian patent n° 102015000057717) and SCENT A1 (Italian patent n° RM2014A000595, European patent n° 3210013), both hosting an array of different sensors based on different active material blends (mixtures of tin, titanium, tungsten, tantalum, niobium, vanadium oxides). The sensor choice for the bio-medical field applications has been performed after several laboratory tests (at Laboratorio Sensori, Department of Physics, University of Ferrara), highlighting the sensor suitability for VOC-detection with the best compromise between sensitivity and specificity parameters. The attained results have been rather encouraging, highlighting the capability of sensors of distinguishing among feces, blood, and tumor tissues collected from CRC-affected subjects and the healthy subject ones, taken as controls (young and without relevant risk factors), by comparing the sensor response patterns. The tests carried out on immortalized cells underlined the dependence of the sensor responses on the cells type, on their initial plating concentration and on the incubation period length (24-48-72 hours). Moreover, the renewed SCENT device has been described (Chapter 5). It starts from the enclosure re-design (with consequent internal spaces rearrangement) and follows with the electronic system and management software re-design and production. The electronic system (most renewed device part) has been readapted exploiting the last generation electronic components, that exhibit a very low electronic noise and an excellent signal-to-noise ratio. Their employment, besides improving the device stability and reliability, allays the internal device overheating. Finally, a new study has been started at the end of 2020, aimed to carry out a follow-up protocol for CRC patients. It consists in the analysis of four blood samples during the post-surgery period. This process should allow a dynamic monitoring of the patient health status and the detection of possible relapses

Stabilization for a Class of Bilinear Systems:A Unified Approach

This letter studies nonlinear dynamic control design for a class of bilinear systems to asymptotically stabilize a given equilibrium point while fulfilling constraints on the control input and state. We design a controller based on integral actions on the system input and output. As special cases, the proposed controller contains a dynamic controller with an integral action of either input or output only and a static controller. Stability analysis of the closed-loop system is performed based on a Lyapunov function. Level sets of the Lyapunov function are utilized to estimate a set of initial states and inputs such that the corresponding state and input trajectories are within specified compact sets. Finally, the proposed control technique is applied to a heat exchanger under constraints on the temperature of each cell (state) and the mass flow rate (input), and simulations show the effectiveness of the proposed approach.</p

Stabilization for a Class of Bilinear Systems:A Unified Approach

This letter studies nonlinear dynamic control design for a class of bilinear systems to asymptotically stabilize a given equilibrium point while fulfilling constraints on the control input and state. We design a controller based on integral actions on the system input and output. As special cases, the proposed controller contains a dynamic controller with an integral action of either input or output only and a static controller. Stability analysis of the closed-loop system is performed based on a Lyapunov function. Level sets of the Lyapunov function are utilized to estimate a set of initial states and inputs such that the corresponding state and input trajectories are within specified compact sets. Finally, the proposed control technique is applied to a heat exchanger under constraints on the temperature of each cell (state) and the mass flow rate (input), and simulations show the effectiveness of the proposed approach.</p