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BackgroundAt present, the prognostic significance of programmed cell death receptor ligand 1 (PD-L1) expression in oropharyngeal squamous cell carcinoma (OPSCC) patients is still controversial. In this study, we aim to synthesize relevant studies that have assessed the prognostic value of PD-L1 in patients with primary OPSCC treated according to the current standard-of-care.MethodsA systematic search of Medline/PubMed, Cochrane, Embase, Web of Science, and Scopus was conducted to define the prognostic role of PD-L1 expression in OPSCC. All studies published before July 31, 2021 were screened. Summary hazard ratios (sHR) with 95% confidence intervals (CIs) were calculated using a random-effects model.ResultsA total of 1522 OPSCC patients from 12 studies were included. PD-L1 expression in OPSCC tumor cells (TCs) was significantly associated with longer overall survival (sHR=0.63, 95% CI 0.50-0.79), and progression-free survival (sHR=0.62, 95% CI 0.49-0.79). A benefit in survival was also observed in PD-L1-positive OPSCC patients who underwent surgery (sHR=0.34, 95% CI 0.18-0.65). Finally, although PD-L1-positive expression was related to better outcomes both in HPV-negative and HPV-positive OPSCC, the difference reached the statistical significance only in the HPV-positive subgroup (sHR=0.37, 95% CI 0.19-0.73). No heterogeneity emerged between studies for all considered outcomes, with I2 ranging from 0% for progression-free survival to 11% for overall survival.ConclusionsPD-L1 expression on TCs associated with improved survival in OPSCC. In particular, HPV-positive OPSCC most benefited from PD-L1 expression when compared to the PD-L1 negative counterpart. Thus, PD-L1 might represent a useful biomarker to stratify prognosis in OPSCC in addition to HPV status.

This paper presents an open source framework called Creamino . It consists of an Arduino-based cost-effective quick-setup EEG platform built with off-the-shelf components and a set of software modules that easily allow users to connect this system to Simulink or BCI-oriented tools (such as BCI2000 or OpenViBE) and set up a wide number of neuroscientific experiments. Creamino is capable of processing multiple EEG channels in real-time and operates under Windows, Linux, and Mac OS X in real-time on a standard PC. Its objective is to provide a system that can be readily fabricated and used for neurophysiological experiments and, at the same time, can serve as the basis for development of novel BCI platforms by accessing and modifying its open source hardware and software libraries. Schematics, gerber files, bill of materials, source code, software modules, demonstration videos, and instructions on how to use these modules are available free of charge for research and educational purposes online at https://github.com/ArcesUnibo/creamino . Application cases show how the system can be used for neuroscientific or BCI experiments. Thanks to its low production cost and its compatibility with open-source BCI tools, the system presented is particularly suitable for use in BCI research and educational applications.

Background: The Prognostic Nutritional Index (PNI) is a parameter of nutritional and inflammation status related to toxicity in cancer treatment. Since data for head and neck cancer are scanty, this study aims to investigate the association between PNI and acute and late toxicity for this malignancy. Methods: A retrospective cohort of 179 head and neck cancer patients treated with definitive radiotherapy with induction/concurrent chemotherapy was followed-up (median follow-up: 38 months) for toxicity and vital status between 2010 and 2017. PNI was calculated according to Onodera formula and low/high PNI levels were defined according to median value. Odds ratio (OR) for acute toxicity were calculated through logistic regression model, hazard ratios (HR) for late toxicity and survival were calculated through the Cox proportional hazards model. Results: median PNI was 50.0 (interquartile range: 45.5–53.5). Low PNI was associated with higher risk of weight loss &gt, 10% during treatment (OR = 4.84, 95% CI: 1.73–13.53 for PNI &lt, 50 versus PNI ≥ 50), which was in turn significantly associated with worse overall survival, and higher risk of late mucositis (HR = 1.84, 95% CI:1.09–3.12). PNI predicts acute weight loss &gt, 10% and late mucositis. Conclusions: PNI could help clinicians to identify patients undergoing radiotherapy who are at high risk of acute and late toxicity.

The characterization of circulating tumor cells (CTCs) is now widely studied as a promising source of cancer-derived biomarkers because of their role in tumor formation and progression. However, CTCs analysis presents some limitations and no standardized method for CTCs isolation from urine has been defined so far. In fact, besides blood, urine represents an ideal source of noninvasive biomarkers, especially for the early detection of genitourinary tumors. Besides CTCs, long noncoding RNAs (lncRNAs) have also been proposed as potential noninvasive biomarkers, and the evaluation of the diagnostic accuracy of urinary lncRNAs has dramatically increased over the last years, with many studies being published. Therefore, this review provides an update on the clinical utility of urinary lncRNAs as novel biomarkers for the diagnosis of bladder and prostate cancers.

Electrical impedance tomography is a noninvasive and cost-effective imaging method that is increasingly attractive in the field of medical diagnostics. Several health conditions, such as stroke and solid tumors, are characterized by compact conductivity anomalies surrounded by a fairly regular background. Commonly employed voxel-by-voxel reconstruction methods for impedance imaging share the disadvantages of high computational cost and substantial sensitivity to measurement noise and imperfections in the electrical model describing the domain of interest. We present a special purpose algorithm for automatic detection and identification of compact conductivity variations. The technique exploits a priori structural information and, by reconstructing only the limited number of parameters required to describe a compact conductivity contrast, does not depend on a critical regularization parameter. The most demanding kernels are implemented to run on graphics processing units to accelerate computation. The parametric reconstruction is quicker and more robust than widely employed approaches with respect to measurement noise and imperfections in the electrical model, as shown by computational analysis performed on a segmented head domain and experimental measurements acquired on a cylindrical phantom. When the goal is quick detection of compact conductivity contrasts in complex 3-D domains, the inclusion of specific constraints relating to the problem considered leads to enhanced quality of reconstruction, making the presented technique a promising alternative to common voxel-by-voxel reconstruction methods.

This paper investigates the effect of tracking errors in heliostats used in solar tower power plants and proposes an approach based on low-cost distributed electronics capable of limiting their impact. An analysis carried out through a parallel model sets the specifications for design of a closed-loop solar tracker based on a low-cost six-axis digital e-compass. A proof of concept system is devised to test the accuracy of the proposed strategy. This approach allows the solar tracker to perform a run-time detection and correction of heliostat tracking errors, with an accuracy of about 3mrad for the azimuth angle and less than 2mrad for the altitude angle, thus leading to a higher concentration ratio than with an open-loop solar-tracker.

Traumatic spinal cord injury has dramatic consequences and a huge social impact. We propose a new mouse model of spinal trauma that induces a complete paralysis of hindlimbs, still observable 30 days after injury. The contusion, performed without laminectomy and deriving from the pressure exerted directly on the bone, mimics more closely many features of spinal injury in humans. Spinal cord was injured at thoracic level 10 (T10) in adult anesthetized female CD1 mice, mounted on stereotaxic apparatus and connected to a precision impactor device. Following severe injury, we evaluated motor and sensory functions, and histological/morphological features of spinal tissue at different time points. Moreover, we studied the effects of early and subchronic administration of Docosahexaenoic acid, investigating functional responses, structural changes proximal and distal to the lesion in primary and secondary injury phases, proteome modulation in injured spinal cord. Docosahexaenoic acid was able i) to restore behavioural responses and ii) to induce pro-regenerative effects and neuroprotective action against demyelination, apoptosis and neuroinflammation. Considering the urgent health challenge represented by spinal injury, this new and reliable mouse model together with the positive effects of docosahexaenoic acid provide important translational implications for promising therapeutic approaches for spinal cord injuries.

Traumatic spinal cord injury has dramatic consequences and a huge social impact. We propose a new mouse model of spinal trauma that induces a complete paralysis of hindlimbs, still observable 30 days after injury. The contusion, performed without laminectomy and deriving from the pressure exerted directly on the bone, mimics more closely many features of spinal injury in humans. Spinal cord was injured at thoracic level 10 (T10) in adult anesthetized female CD1 mice, mounted on stereotaxic apparatus and connected to a precision impactor device. Following severe injury, we evaluated motor and sensory functions, and histological/morphological features of spinal tissue at different time points. Moreover, we studied the effects of early and subchronic administration of Docosahexaenoic acid, investigating functional responses, structural changes proximal and distal to the lesion in primary and secondary injury phases, proteome modulation in injured spinal cord. Docosahexaenoic acid was able i) to restore behavioural responses and ii) to induce pro-regenerative effects and neuroprotective action against demyelination, apoptosis and neuroinflammation. Considering the urgent health challenge represented by spinal injury, this new and reliable mouse model together with the positive effects of docosahexaenoic acid provide important translational implications for promising therapeutic approaches for spinal cord injuries.

This paper presents a different method for measuring the efficiency and the lifetime of a battery cell, that are two of the most important features for the development of hybrid and fully electric vehicles since they affect the performance of the whole system. The IEC 62660–1 is the current automotive standard procedure used to measure them, but it is not sufficient to evaluate all the performances of a cell, especially in a real scenario. The presented method allows to obtain a more accurate measure and a map of the efficiency with respect to the lifetime, reducing the number of tests and using a more realistic dynamic stress cycle. The proposed procedure has been tested on LiFePO 4 cell in order to show the difference with respect to the IEC standard.

The computing demand of many signal processing algorithms is dramatically growing because of the increasing complexity of embedded software applications. Concurrently, as process technology scales, the design effort for realizing very large scale integrated circuits and the associated costs are becoming critically high. A possible solution to address this per- formance/costs challenge is given by customizable multiprocessor system-on-chips. The approach proposed in this paper leads to the customization of multi/many processor system-on-chip at two levels of abstraction: 1) customization through application- specific hardware accelerators implemented on configurable datapath that can target three kinds of structured application- specific integrated circuit technologies: metal, via, and runtime programmable and 2) customization of the architectural para- meters of the platform. The proposed platform is equipped with a design framework that assists the user in the high-level design- space exploration of signal processing applications described using the Open Computing Language (OpenCL) language. A peculiar added value of the flow is to support the migration of OpenCL kernels and tasks into pipelined hardware accelerators described using a C-level language. The platform is able to provide an average performance of 90 GOPS on a set of reference signal processing applications, and an average computational energy efficiency of 130 GOPS/W in its metal-programmable configuration. This result shows the benefits in terms of energy efficiency of hardware customization applied to multiprocessor systems with respect to many core devices such as general- purpose graphic processing units, able to provide on average 2.5 GOPS/W for the applications under analysis.

There has been a fast progress in clinical use of antibody-based immunotherapy, given the superior efficacy commonly achieved in clinic and the limited toxicity. However, personalization of treatment remains of major importance, both to achieve better clinical performance for monotherapy and to identify the best combinations on a patient-by-patient basis. Predicting patient's response is complex due to the need to characterize both tumor response and immunologic mechanisms possibly activated by the therapy, including antibody dependent cellular cytotoxicity (ADCC). We present the Inter-Cell Networking Profiling (ICNP), a novel analytical method enabling a comprehensive and precise characterization of the modulatory effect of immunotherapies on immune-tumor cell interactions. ICNP works on the Open Microwell (OMW) microfluidic system which recreates 20,000 unique cell clusters from ex-vivo patient samples and exposes them to anticancer drugs. We validated the ICNP using multiple myeloma (MM) patient samples to characterize the efficacy of Daratumumab, an anti-CD38 antibody (Ab). Bone marrow samples in EDTA were collected from 11 MM patients. 8 samples were processed by Ficoll-Paque, preserving the original composition of effector (E) and target (T) cells, i.e. NK and plasma cells respectively. 3 samples were processed to obtain co-cultures of WBC depleted of plasma cells (which include NK cells) and U-266 MM cell line. NK and plasma cells were stained with anti-CD16/CD56 and anti-CD138 fluorescently-labeled Abs, respectively. Propidium Iodide (PI) was used as death marker. A statistical model was created to project the optimal experimental setup (E:T ratio, cell concentration) to maximize the co-localization of E/T cells in the 20,000 microwells of the OMW platform. After seeding, cells were incubated with Daratumumab 10µg/mL or no drug and analyzed through fluorescence time lapse microscopy for up to 12 hours. ICNP analysis first separates microwells with both E/T cells in close proximity from those not featuring both cell types (Fig 1A). Then, anti-CD38 efficacy is evaluated in microwells with E/T co-localization, thus implementing a miniaturized ADCC assay (Fig 1B). At the same time, spontaneous NK activity is measured in microwells with E/T co-localization and no drug, while direct effect of the drug on target cells can be measured in microwells with T but not E cells. We first validated our statistical model of co-localization in microwells against the actual number of wells with E/T co-localization (correlation R2: 0.79-0.97, n=5). Then, we characterized the immune composition of 8 MM patients samples with the OMW, finding that E/T cell fractions were in the ranges 5-21% (E) and 1-28% (T). Interestingly, according to our statistical model, co-localization occurs in at least 1% of microwells for all the 8 samples, making ICNP applicable with good statistical significance in the OMW system on ex-vivo clinical samples without any pre-enrichment. Finally, ICNP was evaluated on 4 cases (3 obtained by mixing patient's WBC with U-266 MM cell line and 1 complete MM patient sample). We measured the effect of anti-CD38 Ab using i) the standard approach, considering all microwells regardless of the co-presence of E and T; ii) ICNP approach, considering only microwells featuring E/T co-localization. Results show that drug effect is much evident with ICNP in all the 4 cases with an average increase in target cell death of 40%, indicating a higher sensitivity of this approach than the averaged analysis (Fig 1C, right). Importantly, in one case, the standard analysis did not identify significant differences between anti-CD38 treated and control cells, that could instead be observed with ICNP (p ICNP proved to enable a comprehensive profiling of the immune system by evaluating in one test the immune composition and the fitness of immune cells, both native and drug-treated. These results open the opportunity to develop functional precision medicine approaches for predicting patient's response to drugs with immune-mediated mechanisms of action. AB and RR equally contributed Figure 1 Disclosures Bettelli: CellPly.S.r.l.: Employment. Ruggiano:Cellply S.r.l.: Employment. Bocchi:CellPly S.r.l.: Employment. Rocchi:CellPly.S.r.l.: Employment. Faenza:CellPly S.r.l.: Employment. Zamagni:Janssen: Honoraria, Other: Advisory board, Speakers Bureau; Amgen: Honoraria, Other: Advisory board, Speakers Bureau; BMS: Honoraria, Other: Advisory Board, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Sanofi: Honoraria, Other: Advisory Board, Speakers Bureau; Celgene Corporation: Honoraria, Other: Advisory board, Speakers Bureau. Bettelli:CellPly S.r.l.: Employment. Rambelli:CellPly S.r.l.: Employment. Guadagnuolo:CellPly S.r.l.: Employment. Pecorari:CellPly S.r.l.: Employment. Giulianelli:CellPly S.r.l.: Employment. Pisani:CellPly S.r.l.: Employment. Biscarini:CellPly S.r.l.: Employment. Cavo:amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; bms: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, Speakers Bureau; sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; novartis: Honoraria; takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Guerrieri:CellPly S.r.l.: Equity Ownership. Bocchi:CellPly S.r.l.: Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

This paper presents a power-aware scheduling algorithm based on efficient distribution of the computing workload to the resources on heterogeneous CPU-GPU architectures. The scheduler manages the resources of several computing nodes with a view to reducing the peak power. The algorithm can be used in concert with adjustable power state software services in order to further reduce the computing cost during high demand periods. Although our study relies on GPU workloads, the approach can be extended to other heterogeneous computer architectures. The algorithm has been implemented in a real CPU-GPU heterogeneous system. Experiments prove that the approach presented reduces peak power by 10 percent compared to a system without any power-aware policy and by up to 24 percent with respect to the worst case scenario with an execution time increase in the range of 2 percent. This leads to a reduction in the system and service costs.

Background: Patient stratification to match individual patients with the most effective drug treatment is still a major open challenge in cancer care. For instance, cytarabine is the main drug used for AML treatment but 30% of patients fail to respond to this agent. Laboratory developed tests determining ex-vivo cellular response to cytotoxic anticancer drugs have demonstrated good correlations with clinical response, sometimes surpassing the predictive power of molecular and genetic profiling. Standardizing sample processing to remove operator-dependent biases and maintaining live cells in a functional status that closely resembles in-vivo function are major challenges affecting these tests. Here we present the open microwell (OMW) platform, a microfluidic-based system that integrates the entire process of ex-vivo testing of anticancer drug efficacy and enables drug testing in the clinical setting prior to therapy administration. The concept was validated for the first time on 13 AML patients at Sant'Orsola hospital, Italy, showing the possibility to initiate the analysis readily after sample collection, thus minimizing drifts in cell function that typically start occurring within hours from sampling, and provide results in about 24 hours, with a fully-automated system. Methods: 13 refractory, relapsed or newly diagnosed AML patients were enrolled in the study. 2 ml of fresh bone marrow in EDTA and 1 ml of serum blood were collected from each patient. White blood cells (WBC) were separated from bone marrow by standard Ficoll-Paque, suspended in medium additioned with 2% autologous serum and loaded in microfluidic chips featuring 16 microchannels and 1200 microwells/channel (70 μm diameter), open at the bottom end (Fig. 1A-B). After settling down in microwells, cells were stained with CMAC cell tracker, anti-human-CD34/CD45 fluorescently-labeled antibodies and Propidium Iodide (PI) by injecting the reagents in the microchannels. Cytarabine or combination therapies (FLAI-3, FLAI-5, FLA, MEC-4) were then injected in the microchannels and cells were incubated for 24 hours in the system (Fig. 1C). Four channels were used per therapeutic condition, including reference (ref), high (ref x 10) and low (ref/10) dosages plus a non-treated channel as reaction control. Finally, a custom software was used to detect cells in images, classify AML blasts and analyze cell death (Fig. 1D). Drug efficacy was determined by evaluation of both cell depletion and apoptosis induction. Results: We first validated the OMW platform against gold standard (FacsAria flow cytometer) for the detection of tumor cells and measurement of cell viability and apoptosis. Count of blast frequency was carried out on 5 patient samples using anti-CD34/CD45 staining. Results (Fig. 2B) show a correlation between the gold standard and OMW (n=5, R2=0.99, p Conclusion: The OMW platform was able to count AML blasts and analyze viability and apoptosis showing high concordance with conventional diagnostics represented by flow cytometry. The assay requires 30 μl of bone marrow sample and simple manual pre-processing. Profiling of patient response to specific drugs or combination is provided within 24h. These features make the OMW platform suitable for bedside analysis, to evaluate drug activity on tumor cells within a heterogeneous sample and promptly guide personalized treatment in hematologic malignancies, with a first proof achieved on AML patients. LRo and AF equally contributed. Disclosures Rocchi: CellPly S.r.l.: Employment. Faenza:CellPly S.r.l.: Employment. Rambelli:CellPly S.r.l.: Employment. Guadagnuolo:CellPly S.r.l.: Employment. Pecorari:CellPly S.r.l.: Employment. Giulianelli:CellPly S.r.l.: Employment. Biscarini:CellPly S.r.l.: Employment. Martinelli:Novartis: Speakers Bureau; Roche: Consultancy, Speakers Bureau; Ariad: Consultancy, Speakers Bureau; BMS: Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; MSD: Consultancy; Celgene: Consultancy, Speakers Bureau; Genentech: Consultancy. Guerrieri:CellPly S.r.l.: Equity Ownership. Bocchi:CellPly S.r.l.: Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

This paper describes a System on Chip implementation of a reconfigurable digital signal processor. The device is suitable for execution of a wide range of applications exploiting a balanced mix of heterogeneous reconfigurable fabrics merged together by a flexible and efficient communication infrastructure based on a 64-bit Network On Chip. The SoC combines a fine grain embedded FPGA, a mid grain configurable processor and a coarse grain reconfigurable array. An ARM processor featuring a resident operating system is the SoC supervisor, managing communication, synchronization and reconfiguration mechanisms. This computational model enables the programmer to manage the high level synchronization and global data of complex signal processing applications through the ARM processor, while allocating most critical computational kernels to the most suitable reconfigurable engines. The SoC has been fabricated in 90-nm technology, the die area being 110 mm2; it integrates 97 million transistors and has a peak power consumption of 2.5 W. In order to demonstrate the proposed computational model and the reconfigurable signal processor capabilities in a real test case, a video surveillance motion detection application was implemented in the SoC. When running this application, the device proved able to deliver 120 GOPS dissipating 1.45 W.

Functional profiling is an emerging trend in precision medicine. Manual laboratory methods proved to be effective in predicting the response to drug treatments both in patients stratified according to genetic profiling and in patients without any specific molecular aberration. In this work, we validated the predictive power of an innovative functional profiling platform, based on lab-on-a-chip technology, which allows testing the response of live tumor cells exposed to anticancer drugs in a fully-automated process, requiring only a Ficoll stratification as a manual step. 15 AML patients (Age: 40% 70 years; Gender: 40% Female; ELN Classification: 20% Favorable, 26% Intermediate-I, 33% Intermediate-II, 14% Adverse; AML stage: 53% De novo, 7% Relapse, 40% Refractory; Treatment: 20% FLAI-3, 40% FLAI-5, 26% Decitabine; 7% Cytarabine, 7% 5-azacitidine) were treated at the Policlinico Sant'Orsola in Bologna. At the same time, bone marrow samples were challenged with the same drugs at scaled concentrations in the functional profiling platform developed by CellPly and an output score was extracted from time-lapse fluorescence image analysis of patient tumor cells exposed to the drug or drug combination for 24 hours. Clinical follow up resulted in the following classification: complete hematologic response (CR) was found in 6/15 patients (6/6 with a De Novo disease), while the remaining 9/15 patients (2/9 de novo; 1/9 Relapse; 6/9 Refractory) were classified as stable disease (SD). In-vitro functional profiling of 14 patients provided a correlation with the clinical outcome (p=0.01) irrespective of the stage of the disease. 100% of the patients identified as responders by functional profiling (n = 5), resulted in a CR outcome. 89% of the patients identified as non-responders (n = 9) resulted in an SD outcome. The same patient samples were also investigated for the molecular assessment of the most relevant genes commonly analyzed in AML patients. FLT3-ITD mutation was found in 2/14 patients, both in SD. Negative FLT3 was not correlated to clinical outcome. FLT3-TKD mutation was found in 3/14 patients, 2/3 resulted in CR, 1/3 in SD. TP53 mutation was found in 1/13 patients, classified as SD. Intronic variant rs1625895 was found in 6/13 patients equally distributed in CR and SD. NPM1 mutation was identified in 4/13 patients, 2/4 resulted in CR, 2/4 in SD indicating no direct correlation. IDH2 was found in 1/11 patients (with R172K mutation) with an SD. As a conclusion, functional profiling proved to be highly correlated with clinical outcome irrespective of patient stage and demonstrated a superior predictive power compared to molecular profiling. Citation Format: Laura Rocchi, Andrea Faenza, Viviana Guadagnuolo, Laura Rambelli, Giovanni Marconi, Maria Chiara Fontana, Martina Pazzaglia, Cristina Papayannidis, Giorgia Simonetti, Nicola Pecorari, Luca Giulianelli, Dario Biscarini, Marco Bettelli, Michele Federici, Rita Ruggiano, Giovanni Martinelli, Roberto Guerrieri, Massimo Bocchi. Lab-on-a-chip-based in-vitro functional profiling proves to be effective in predicting therapy outcome in AML patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3613.

Background: A strategy to reduce the secondary effects of anti-cancer agents is to potentiate the therapeutic effect by their combination. A combination of vitamin K3 (VK3) and ascorbic acid (AA) exhibited an anti-cancer synergistic effect, associated with extracellular production of H2O2 that promoted cell death. Methods: The redox-silent vitamin E analogue α-tocopheryl succinate (α-TOS) was used in combination with VK3 and AA to evaluate their effect on prostate cancer cells. Results: Prostate cancer cells were sensitive to α-TOS and VK3 treatment, but resistant to AA upto 3.2 mM. When combined, a synergistic effect was found for VK3–AA, whereas α-TOS–VK3 and α-TOS–AA combination showed an antagonist and additive effect, respectively. However, sub-lethal doses of AA–VK3 combination combined with a sub-toxic dose of α-TOS showed to induce efficient cell death that resembles autoschizis. Associated with this cell demise, lipid peroxidation, DNA damage, cytoskeleton alteration, lysosomal–mitochondrial perturbation, and release of cytochrome c without caspase activation were observed. Inhibition of lysosomal proteases did not attenuate cell death induced by the combined agents. Furthermore, cell deaths by apoptosis and autoschizis were detected. Conclusion: These finding support the emerging idea that synergistic combinations of some agents can overcome toxicity and other side-effects associated with high doses of single drugs creating the opportunity for therapeutically relevant selectivity.

This review paper summarizes some of the most challenging issues regarding the development of electronic microsystems for the isolation, manipulation, and characterization of rare cells. Two relevant areas, namely, immunology for cancer therapy and monitoring of microbial contaminants in water, are presented as example applications which require handling of rare cells. Starting from these applications, the state of the art in electronic microsystem research is presented, and various solutions are discussed, highlighting the advantages and disadvantages of each technology and suggesting the need to integrate multiple solutions to meet the application requirements.

The paper presents a novel Driving Right Leg (DgRL) circuit designed to mitigate the effect of common mode signals deriving, say, from power line interferences. The DgRL drives the isolated ground of the instrumentation towards a voltage which is fixed with respect to the common mode potential on the subject, therefore minimizing common mode voltage at the input of the front-end. The paper provides an analytical derivation of the common mode rejection performances of DgRL as compared to the usual grounding circuit or Driven Right Leg (DRL) loop. DgRL is integrated in a bio-potential acquisition system to show how it can reduce the common mode signal of more than 70 dB with respect to standard patient grounding. This value is at least 30 dB higher than the reduction achievable with DRL, making DgRL suitable for single-ended front-ends, like those based on active electrodes. EEG signal acquisition is performed to show how the system can successfully cancel power line interference without any need for differential acquisition, signal post-processing or filtering.

We present a system for the acquisition of EEG signals based on active electrodes and implementing a Driving Right Leg circuit (DgRL). DgRL allows for single-ended amplification and analog-to-digital conversion, still guaranteeing a common mode rejection in excess of 110 dB. This allows the system to acquire high-quality EEG signals essentially removing network interference for both wet and dry-contact electrodes. The front-end amplification stage is integrated on the electrode, minimizing the system's sensitivity to electrode contact quality, cable movement and common mode interference. The A/D conversion stage can be either integrated in the remote back-end or placed on the head as well, allowing for an all-digital communication to the back-end. Noise integrated in the band from 0.5 to 100 Hz is comprised between 0.62 and 1.3 µV, depending on the configuration. Current consumption for the amplification and A/D conversion of one channel is 390 µA. Thanks to its low noise, the high level of interference suppression and its quick setup capabilities, the system is particularly suitable for use outside clinical environments, such as in home care, brain-computer interfaces or consumer-oriented applications.

Chip-to-chip interconnection, based on wireless communication by capacitive coupling was investigated. This innovative approach will considerably reduce the pitch of the pin and strongly help in the implementation of a dense network of interconnects, while improving inter-chip bandwidth and power dissipation. The 3D integration technology based on aligned wafer-to-wafer direct bonding technique was implemented for IC capacitive interconnection realization. The capacitive structures are created by facing two wafers with symmetrical IC chips bearing at last level a two-dimensional array of metal arms covered by a dielectric layer. Communication take place by capacitive coupling using capacitors created at location in the aligned micro-array. The capacitance dielectric thickness was monitored during the wafer bonding. Specific wafer process flow and especially precise circuit alignment were applied; in order to create between the bonded chips the capacitive interconnect arrays. After bonding, one wafer was thinned down, and I/O via were opened though the piled up remaining silicon and the two bonded stacks of CMOS structures. That elaborated structure was then ready for wire bonding. Electrical characterization tests are performed and the first functional testing gives very good performances in high-speed communication between the stacked chips.

This paper presents a novel approach to continuously measure the mechanical deformations of a tire due to contact with asphalt, by embedding capacitive–resistive sensors in it. A strain monitoring method is proposed, which adopts the tire itself as a sensing element. In this way, the sensing area is pushed towards the tread interface (the part of the tire in direct contact with the asphalt), where the information concerning tire state is actually generated. Tire deformation causes a change of the spacing between the steel wires inside the tire carcass and this change is translated into an impedance change of that region of the tire. By measuring such an impedance change, our approach makes it possible to determine the deformation of the tire. Static stress–strain measurements show a linearity of about 80% in the impedance–strain relation. A linear impulse of tensile strain has been used to validate the detection of instantaneous changes in the tread–asphalt interface. The mechanical solicitation resulted in a 1% deformation of the specimen’s main dimension. Experimental results report a change of about 40% in the real part of the impedance and a change of about 20% in the imaginary part of the impedance. The same measurements have been performed varying the temperature within a range of −20 to 90 ◦C, which is compatible with the operating conditions of a commercial car tire.

This paper describes a wired addressing architecture of distributed sensors for monitoring real-time in situ pressure variations in underwater environment. Limits of isolated sensors and drawbacks of acoustic communication are overcome, and an application to the inspection of a submerged structure is made feasible. The prototype sensor is a Kapton®-based three-layered structure. We fabricated a 0.18 μm CMOS mixed-mode System on Chip (SoC) as a prototype and a five-pad Chip on Board (COB) for unobtrusive monitoring. Testing sessions in aquatic environment have been carried on, and the dependence of the capacitance on pressure variation is shown when a linear pressure variation is exerted. An experimental result in a turbulent operating condition is reported too.

In this letter, the implementation of a system-on-chip for the documentation of road accidents is presented. Key features of the system are the implementation on a programmable architecture of a compression algorithm capable of encoding up to 20 black and white QCIF frames/s, and the computation of a digital signature performed every frame which is applied to the encoded bitstream certifying the source of the video sequence. The acquired images are then stored on a battery of on-chip flash memories that can be used to retrieve accident information to be used in legal confrontations. Having to perform in critical energy conditions (e.g., continued image acquisition for up to 10-20 s after an accident has occurred), the system was designed to minimize energy consumption at all levels. The system-on-chip has been implemented in 6/spl times/6 mm/sup 2/ on a 0.25-/spl mu/m 6-metal standard-cell CMOS technology and works at 40 MHz with a 2.5-V power supply. Performance can be decreased to 12 QCIF frames/s, 24 MHz, and 1.3-V power supply in order to achieve 30-mW power consumption.

The development of microfabricated devices manufactured in silicon, glass, or plastic materials is a well-known trend in the research of novel biological techniques and tools over the last two decades, resulting in a multitude of start-up companies serving the pharmaceutical, biotechnology, and diagnostics markets. However, the idea of implementing such devices on microelectronic substrates has been introduced only recently. This chapter aims to describe the state-of-the-art of microsystems for molecular and cell biology produced in general purpose CMOS (complementary metal oxide semiconductor) technology, emphasizing the advantages of this approach along with their challenges and limitations. This chapter discusses significant examples of fully tested devices in comparison with existing state-of-the-art techniques.

This paper presents a mixed-signal system-on-chip (SOC) for sensing capacitance variations, enabling the creation of pressure-sensitive fabric. The chip is designed to sit in the corner of a smart fabric such as elastic foam overlaid with a matrix of conductive threads. When pressure is applied to the matrix, an image is created from measuring the differences in capacitance among the rows and columns of fibers patterned on the two opposite sides of the elastic substrate. The SOC approach provides the flexibility to accommodate for different fabric sizes and to perform image enhancement and on-chip data processing. The chip has been designed in a 0.35-/spl mu/m five-metal one-poly CMOS process working up to 40 MHz at 3.3 V of power supply, in a fully reconfigurable arrangement of 128 I/O lines. The core area is 32 mm/sup 2/.

In this study we describe an original, efficient, and innovative printed circuit board (PCB) device able to generate dielectrophoresis-based, software-controlled cages that can be moved to any place inside a microchamber. Depending on their dielectrophoretic properties, eukaryotic cells can be “entrapped” in cages and moved under software control. The main conclusion gathered from the experimental data reported is that the PCB device based on dielectrophoresis permits levitation and movement of different tumor cells at different dielectrophoresis conditions. The results presented herein are therefore the basis for experiments aimed at forced interactions or separation of eukaryotic cells using “lab-on-a-chip.” In fact, because many cages can be controlled at the same time, and two or more cages can be forced to share the same or a different location, it is possible, in principle, either to bring in contact cells of a differing histotype or to separate them. © 2003 Wiley Periodicals, Inc. Biotechnol Bioeng 82: 474–479, 2003.

The IC presented integrates the front-end for EEG and Electrical Impedance Tomography (EIT) acquisition on the electrode, together with electrode-skin contact impedance monitoring and EIT current generation, so as to improve signal quality and integration of the two techniques for brain imaging applications. The electrode size is less than 2 ${\rm cm}^{2}$ and only 4 wires connect the electrode to the back-end. The readout circuit is based on a Differential Difference Amplifier and performs single-ended amplification and frequency division multiplexing of the three signals that are sent to the back-end on a single wire which also provides power supply. Since the system's CMRR is a function of each electrode's gain accuracy, an analysis is performed on how this is influenced by mismatches in passive and active components. The circuit is fabricated in 0.35 $\mu {\rm m}$ CMOS process and occupies 4 ${\rm mm}^{2}$ , the readout circuit consumes 360 $\mu {\rm W}$ , the input referred noise for bipolar EEG signal acquisition is 0.56 $\mu {\rm V}_{RMS} $ between 0.5 and 100 Hz and almost halves if only EEG signal is acquired.

This paper describes the implementation of a block-matching module with digital I/O. Algorithmic analysis demonstrates that the precision requirements can be met by a compact circuit that processes the signal in the charge domain. The required conversion between voltages and charges is achieved by MOS capacitors. As a result, it can be fabricated by any inexpensive digital CMOS technology. A test chip has been implemented in a standard CMOS 1.6 μm technology and the measured energy consumption is 1.2 nJ per block match using an 8 \times 8 pixel matrix. Simulations of the same cell in 0.35 μm and 0.25 μm CMOS technology are presented, showing the scalability of the approach.

This paper describes a VLSI array processor system designed and built for classification problems based on the k-nearest-neighbors approach. This architecture is suitable for different pattern recognition applications and is very efficient for high-dimensional databases. The architecture is scalable with the size of the recognition problem making the system effectively applicable to computational intensive application like on-line pattern recognition. A system prototype composed of a board with two processors, the software driver and a test application have been built and evaluated. For handwritten character recognition task the complete system shows a speed up of 260 times over a sequential algorithm running on a Sun SPARC20 workstation.

A direct-contact finger mouse realized in 0.7-/spl mu/m digital CMOS is presented. It is based on the motion detection of the fingerprint images acquired with a capacitive sensor. Stroking and tapping the chip surface with the finger causes movement of the cursor and clicking-like mouse. By properly partitioning analog collective computation and digital processing, a power consumption of about 900 /spl mu/W at 5 V is achieved. The sensor area is 3.8/spl times/3.8 mm/sup 2/, and overall chip size is 7.7/spl times/6.7 mm/sup 2/.

In this paper, a low-power, low-voltage, voice-controlled H.263 video decoding system is presented. Its power consumption makes it suitable for portable systems with limited battery resources. Video decoding of quarter-common intermediate format (QCIF) images at 25 frames per second is achieved at 1-MHz clock frequency and requires about 60 /spl mu/W at 1-V power supply, Sub-QCIF and CIF image formats are also supported. The decoder circuit is controlled by the on-chip isolated word speech recognizer. It is used to implement command-oriented and menu-based applications. The resulting system is expandable taking additional external devices under voice control. The chip integrates 650-k transistors in a 36-mm/sup 2/ area and has been implemented using a standard CMOS 0.35-/spl mu/m, five-metal technology process. The system works correctly down to 0.9 V, allowing single-cell button battery operation.

This paper introduces a single-chip, 200/spl times/200-element sensor array implemented in a standard two-metal digital CMOS technology. The sensor is able to grab the fingerprint pattern without any use of optical and mechanical adaptors. Using this integrated sensor, the fingerprint is captured at a rate of 10 F/s by pressing the finger skin onto the chip surface. The fingerprint pattern is sampled by capacitive sensors that detect the electric field variation induced by the skin surface. Several design issues regarding the capacitive sensing problem are reported and the feedback capacitive sensing scheme (FCS) is introduced. More specifically, the problem of the charge injection in MOS switches has been revisited for charge amplifier design.

This paper describes the application space exploration of a heterogeneous digital signal processor with dynamic reconfiguration capabilities. The device is built around three reconfigurable engines featuring different flavours and computation granularities that make it suitable for a wide range of signal processing application domains such as video coding, image processing, telecommunications, and cryptography. Performance of signal processing applications is evaluated from measurements performed on a CMOS 90 nm prototype. In order to characterize the application space of the processor, performance is compared with state-of-the-art devices, taking programmability, computational capabilities, and energy efficiency as the main metrics. The device exploits performance and energy efficiency significantly more than general purpose processors, while still maintaining a user-friendly programming approach that mainly relies on software-oriented languages. The device is able to achieve 1.2 to 15 GOPS with an energy efficiency from 2 to 50 GOPS/W when running the selected applications.

The synthesis of fuzzy systems involves the identification of a structure and its specialization by means of parameter optimization. In doing this, symbolic approaches which encode the structure information in the form of high-level rules allow further manipulation of the system to minimize its complexity, and possibly its implementation cost, while all-parametric methodologies often achieve better approximation performance. In this paper, we rely on the concept of a fuzzy set of rules to tackle the rule induction problem at an intermediate level. An online adaptive algorithm is developed which almost surely learns the extent to which inclusion of a rule in the rule set significantly contributes to the reproduction of the target behavior. Then, the resulting fuzzy set of rules can be defuzzified to give a conventional rule set with similar behavior. Comparisons with high-level and low-level methodologies show that this approach retains the most positive features of both.

In this work we investigate techniques for embedding domain-specific spatial invariances into highly-constrained neural networks. This information is used to drastically reduce the number of weights which have to be determined during the learning phase, thus allowing us to apply artificial neural networks to problems characterized by a relatively small number of available examples. As an application of the proposed methodology, we study the problem of optical inspection of machined parts. More specifically, we have characterized the performance of a network created according to this strategy, which accepts images of parts under inspection at its input and issues a flag at its output which states whether the part is defective. The results obtained so far show that the proposed methodology provides a potentially relevant approach for the quality control of industrial parts, as it offers both accuracy and short software development time, when compared with a classifier implemented using a standard approach.

In this paper, a silicon compiler for analog fuzzy controllers is described. The layout is generated automatically, starting from global-system specifications accepted as a set of classical fuzzy rules involving fuzzy sets as well as numerical data, often available from numerical examples. The system relies on a library of basic cells designed using a CMOS n-well 0.7 /spl mu/m technology and on the use of Cadence software. Multi-inputs multi-outputs fuzzy logic-based controllers are synthesized, and the area and power requirements by any specific application are optimized. Some prototypes designed using the proposed methodology have been fabricated. For example, a two-inputs two-outputs fuzzy controller implementing a 2D rational function and a sinusoidal function requires, including the I/O circuitry, 1.9 mm/sup 2/ of silicon area, and the total power consumption is 44 mW at 5 V power supply. The maximum propagation delay, assuming a step input function, is 0.57 /spl mu/sec. The total computation time using a SUN Sparc2 Workstation is about 25 min, from specification of the expected behavior to layout.

In applications where low cost is the primary concern, analog VLSI controllers are an option. In this paper a hardware and software integrated toolkit for development of analog controllers based on fuzzy logic is presented. The system is composed of a CMOS analog circuit whose input/output relationship can be programmed to synthesize various control functions. The value of the programmable parameters can be automatically computed by the software tool, assuming that the user specifies the controller expected behavior by means of linguistic and/or numeric information. A complete example of how fuzzy linguistic and numerical methodologies can be combined with more conventional techniques to synthesize a nontrivial controller is detailed down to measured data. A final discussion clarifies the main advantages of the fuzzy analog computation when it is supported with an appropriate software layer: nontrivial solutions to problems in which accuracy is not the primary concern can be easily synthesized and integrated into very small silicon areas with small power requirements.

A simple form of cooperation between the k-nearest neighbors (NN) approach to classification and the neural-like property of adaptation is explored. A tunable, high level k-nearest neighbors decision rule is defined that comprehends most previous generalizations of the common majority rule. A learning procedure is developed that applies to this rule and exploits those statistical features that can be induced from the training set. The overall approach is tested on a problem of handwritten character recognition. Experiments show that adaptivity in the decision rule may improve the recognition and rejection capability of standard k-NN classifiers.

A new statistical classifier for handwritten character recognition is presented. After a standard preprocessing phase for image binarization and normalization, a distance transform is applied to the normalized image, converting a black and white (B/W) into a gray scale picture. The latter is used as feature space for a k -Nearest-Neighbor classifier, based on a dissimilarity measure which generalizes the use of the distance transform itself. The classifier has been implemented on a massively-parallel processor, Connection Machine CM-2. Classification results of digits extracted from the U.S. Post Office ZIP code database and the upper-case letters of the NIST Test Data 1 are provided. The system has an accuracy of 96.73% on the digits and 94.51% on the upper-case letters when no rejection is allowed and an accuracy of 98.96%, on the digits and 98.72% on the upper-case letters at 1% error rate.

The two-dimensional massively parallel electromagnetic simulation program TEMPEST has been generalized to extend its applicability to many of the difficult problems in photolithography, metrology, and alignment. TEMPEST, which has been made available on the NCSA and other computing centers, combines together techniques for analysis of the transverse electric (TE) and the transverse magnetic (TM) polarizations, oblique incidence, highly dispersive materials, and a technique for synthesis of partially coherent optical images. The solution is based on the time-domain finite-difference method, but exploits the power of massively parallel computer architectures. Equations suitable for massively parallel implementation are given for oblique incidence, both polarizations and dispersive materials. Computer time per iteration cycle is constant irrespective of the polarization and angle of incidence. However, the total simulation time for convergence was found to be dominated by physical scattering phenomena. Convergence for the TM polarization is 1.5 times slower than the TE polarization because of edge currents, and oblique incidence is 2 times slower than normal incidence owing to artificial reflection from the domain boundaries. A typical simulation time is three to five minutes with 256 k (1 k=1024) simulation nodes on a CM-2 with 8 k processors. The effectiveness of the program for photolithographic applications is demonstrated by considering the effects of subtle changes in phase-shifting mask topography on the optical images. >

The IC presented integrates the front-end for EEG and Electrical Impedance Tomography acquisition on the electrode, together with contact impedance monitoring, so as to improve signal quality and functional integration of the two techniques for brain imaging applications. Only 4 wires connect the electrode to the back-end. The readout circuit consumes 1 mW, while the input referred noise for EEG signal acquisition is 0.45 μVRM S between 0.5 and 100 Hz, doubling when both EEG and EIT are acquired simultaneously.

A memory interface for a 3D System-on-a-Chip based on capacitive coupling is implemented in 90nm CMOS technology. The design choices have been driven by an innovative 3D extraction and simulation flow. The presented work exploits AC capacitive coupling for chip-to-chip communication running up to 250MHz. The interface transfers 128 bit words between stacked SRAMs in an ARM-based System-on-a-Chip (SoC). The 3D memory interface achieves a total throughput of 32Gbit/sec with an average energy consumption of 35uW/Gbit/sec and an area occupancy of 0.05mm square.

3D chip-to-chip capacitive interconnections are in common practice characterized with FEM solvers as they cannot be modeled as lumped RLC circuits as ohmic 3D interconnects. This paper describes some drawbacks of this procedure and proposes an innovative flow, based on post-layout parasitic extraction tools, to enable the designer to place capacitive interconnects as constrained macros in a digital design flow.

An analog frame buffer suitable for early-vision processing is described. It has been fabricated using digital 1.6- mu m CMOS technology. A novel architecture is presented to compensate for the effect of parameter mismatch. The chip stores an image for a time frame of 1/30 s with an equivalent precision of more than 6 b. The array size is 32*32 and the cell dimension is 30.8 mu m*40 mu m. Power consumption is below 30 mW and the chip requires a bias supply of 5 V. >

International audience; This paper describes the RTL-to-Layout implementation of the PACT XPP-III Coarse-Grained Reconfigurable Architecture (CGRA). The implementation activity was strictly based on a hierarchical approach in order to exploit performance optimization at all levels, as well as guarantee maximum scalability and provide a portfolio of IP-blocks that could be reused to build different configurations and embodiments of the same CGRA template. The final result can be seamlessly introduced in any SoC design flow as embedded accelerator. It is designed in STMicroelectronics 90nm GP technology, occupies 42.5 mm2, delivers 13 16-bit GOPS (0.8 GOPS/mW, 10 MOPS/mW) and has a measured max frequency of 150 MHZ, requiring a measured 13 mW/MHz dynamic power, 93 mW static. A silicon prototype was also produced embedding XPP-III in a complex system-on-chip including an ARM processor as system controller as well as different ASIC blocks.

An AC-coupled 3D memory interface for chip-to-chip communication is implemented in 90nm CMOS technology. It transfers 128 bit words between stacked SRAMs in an ARM-based System on Chip (SoC) platform at 250MHz. This interface requires 0.05mm2 of occupation area and achieves a 32Gbit/sec of throughput and an average energy consumption of 35μW/Gbit/sec.

This paper presents a review of the solutions proposed for chip-to-chip communication based on capacitive coupling. Circuit designs, assembly options and various different test cases are presented in this work. It is shown that this 3D technology is capable of transferring digital data between two dies at highspeed with low power consumption, and likewise analog signals without the need for any extrawafer processing. The results presented highlight the key features of capacitive coupling when compared to other 3D interconnections and justify the effort to overcome some open issues and make it a marketable technology.

An architecture to compensate the voltage attenuation introduced by 3D capacitive coupling is proposed. The scheme is applied to the design of a prototype aimed at demonstrating that 3D technology based on capacitive coupling allows to transmit analog signals as well as digital ones. The scheme is based on a calibration channel which sets the gain of the variable gain amplifiers of signal channels in order to compensate for the voltage attenuation. The prototype is designed in CMOS 90 nm technology. 3D assembling is done at die level using a face to face stacking procedure. Each channel has an area 90x30 µm2 and a power consumption of 1 mW. A gain error within 10% with respect to the nominal value has been measured for a signal amplitude varying from 200 mV to 1 V in the 100 KHz to 20 MHz range.

Aim of this study was to investigate the effect of the preparation parameters on the characteristics of lipospheres that would optimally fit to a lab-on-a-chip platform. Lipospheres were produced by melt dispersion technique using different lipid mixture heated to 70 °C and then emulsified into an external aqueous phase. The initial part of the work was devoted to the selection of the best lipid composition by a classical intuitive approach while the optimization and the screening of the experimental parameters were conducted through a “design of experiments”. Once the best preparation parameters were selected, they were adopted also for the production of cationic lipospheres (CLS). The second part of the study describes the analysis of the lipospheres performances when applied to a DEParray™Chip. The loading, distribution, movement and separation of neutral and cationic lipospheres were investigated. The obtained data show that both neutral and cationic lipospheres can be efficiently used in association with DEParray™Chip.

In this work we present a novel concept of active microwells based on cylindrical wells able to vertically trap and control single particles by means of negative dielectrophoresis. The device is fabricated by drilling through holes on a polyimide substrate with copper–gold or aluminum metals, forming three annular electrodes within the well. A channel under the device provides a fluid flow filling the microwell by capillarity. Particles are delivered from the top by a microdispenser and applying sinusoidal signals to the electrodes at frequencies ranging from 100 kHz to 1.5 MHz and amplitudes between 2 V and 7 V they are successfully trapped and levitated at the level of the central electrode in the middle of microwells with a diameter of 125 μm. By changing signal phases, other configurations are also enabled to load particles in the well or eject them from the bottom. The extension to an array of microwells is presented and design rules are described for routing electrode connections and setting signal parameters. K562 cells cultured with Ara-C 1000 nM were successfully trapped and controlled in physiological media. Polystyrene beads were also levitated in water and were used for experimental measurements on minimum amplitudes and phase differences in the signals required to levitate beads, confirming the results obtained by simulation.