Type I IFNs promote cancer cell stemness by triggering the epigenetic regulator KDM1B.

Cancer stem cells (CSCs) are a subpopulation of cancer cells endowed with high tumorigenic, chemoresistant and metastatic potential. Nongenetic mechanisms of acquired resistance are increasingly being discovered, but molecular insights into the evolutionary process of CSCs are limited. Here, we show that type I interferons (IFNs-I) function as molecular hubs of resistance during immunogenic chemotherapy, triggering the epigenetic regulator demethylase 1B (KDM1B) to promote an adaptive, yet reversible, transcriptional rewiring of cancer cells towards stemness and immune escape. Accordingly, KDM1B inhibition prevents the appearance of IFN-I-induced CSCs, both in vitro and in vivo. Notably, IFN-I-induced CSCs are heterogeneous in terms of multidrug resistance, plasticity, invasiveness and immunogenicity. Moreover, in breast cancer (BC) patients receiving anthracycline-based chemotherapy, KDM1B positively correlated with CSC signatures. Our study identifies an IFN-I → KDM1B axis as a potent engine of cancer cell reprogramming, supporting KDM1B targeting as an attractive adjunctive to immunogenic drugs to prevent CSC expansion and increase the long-term benefit of therapy.

The effect of size range on ultrasound-induced translations in microbubble populations.

Microbubble translations driven by ultrasound-induced radiation forces can be beneficial for applications in ultrasound molecular imaging and drug delivery. Here, the effect of size range in microbubble populations on their translations is investigated experimentally and theoretically. The displacements within five distinct size-isolated microbubble populations are driven by a standard ultrasound-imaging probe at frequencies ranging from 3 to 7 MHz, and measured using the multi-gate spectral Doppler approach. Peak microbubble displacements, reaching up to 10 µm per pulse, are found to describe transient phenomena from the resonant proportion of each bubble population. The overall trend of the statistical behavior of the bubble displacements, quantified by the total number of identified displacements, reveals significant differences between the bubble populations as a function of the transmission frequency. A good agreement is found between the experiments and theory that includes a model parameter fit, which is further supported by separate measurements of individual microbubbles to characterize the viscoelasticity of their stabilizing lipid shell. These findings may help to tune the microbubble size distribution and ultrasound transmission parameters to optimize the radiation-force translations. They also demonstrate a simple technique to characterize the microbubble shell viscosity, the fitted model parameter, from freely floating microbubble populations using a standard ultrasound-imaging probe.

Crowd-Based Cognitive Perception of the Physical World: Towards the Internet of Senses.

This paper introduces a possible architecture and discusses the research directions for the realization of the Cognitive Perceptual Internet (CPI), which is enabled by the convergence of wired and wireless communications, traditional sensor networks, mobile crowd-sensing, and machine learning techniques. The CPI concept stems from the fact that mobile devices, such as smartphones and wearables, are becoming an outstanding mean for zero-effort world-sensing and digitalization thanks to their pervasive diffusion and the increasing number of embedded sensors. Data collected by such devices provide unprecedented insights into the physical world that can be inferred through cognitive processes, thus originating a digital sixth sense. In this paper, we describe how the Internet can behave like a sensing brain, thus evolving into the Internet of Senses, with network-based cognitive perception and action capabilities built upon mobile crowd-sensing mechanisms. The new concept of hyper-map is envisioned as an efficient geo-referenced repository of knowledge about the physical world. Such knowledge is acquired and augmented through heterogeneous sensors, multi-user cooperation and distributed learning mechanisms. Furthermore, we indicate the possibility to accommodate proactive sensors, in addition to common reactive sensors such as cameras, antennas, thermometers and inertial measurement units, by exploiting massive antenna arrays at millimeter-waves to enhance mobile terminals perception capabilities as well as the range of new applications. Finally, we distillate some insights about the challenges arising in the realization of the CPI, corroborated by preliminary results, and we depict a futuristic scenario where the proposed Internet of Senses becomes true.

Why methylation is not a marker predictive of response to hypomethylating agents.

The azanucleotides azacitidine and decitabine have been shown to induce hematologic response and prolong survival in higher-risk myelodysplastic syndromes. They are inhibitors of DNA methyltransferase-1 and induce DNA-hypomethylation. Induction of apoptosis is also clinically relevant, in particular during the first treatment cycles, when cytopenia is a frequent side-effect. Since the hypomethylating effect is reversible, and the malignant clone has been shown to persist in most responding patients, several cycles are necessary to achieve and maintain responses, while treatment interruption is associated with rapid relapse. Methylation studies have shown global and gene-specific hypermethylation in myelodysplastic syndromes, but there seems to be little relation between the degree of demethylation following hypomethylating treatment and hematologic response. The presence of concurrent genomic hypermethylation and hypomethylation may impair the predictive power of current detection techniques. This scenario has been complicated by the identification of epigenetic enzyme mutations, including TET2, IDH1/2, DNMT3A and EZH2, which are important for response to hypomethylating treatment. Changes in azanucleotide metabolism genes may also play a role. In the future, methylation analysis concentrating not only on promoters, but also on gene bodies and intergenic regions, may identify key genes in patients with the highest probability of response to azanucleotides and allow a patient-tailored approach.

Bradeion (SEPT4) as a urinary marker of transitional cell bladder cancer: a real-time polymerase chain reaction study of gene expression.

PURPOSE: We evaluated whether Bradeion/SEPT4 gene expression could be used as a potential urinary marker to diagnose bladder transitional cell carcinoma. MATERIALS AND METHODS: From 2005 to 2007 we collected urine samples from 58 individuals, 17 healthy controls and 41 patients in whom bladder tumors were previously diagnosed by cystoscopy. Urine was collected from all patients before transurethral resection of bladder tumor. We performed real-time reverse transcriptase-polymerase chain reaction to evaluate Bradeion/SEPT4 transcript levels using urine sample mRNA. Statistical analysis was done with the Mann-Whitney test and ROC curves. RESULTS: Pathological examination of bladder tumor specimens revealed transitional cell bladder cancer. According to the 2002 TNM classification stage was Ta in 11 patients, T1 in 18 and T2/T3 in 12. All patients had G2 or G3 tumors according to the 1973 WHO grade classification. Relative quantification analysis of Bradeion transcript showed significantly increased levels compared to controls, namely 21.85 times higher in Ta stage tumors, 7.21 times higher in T1 tumors and 4.36 times higher in grade T2/T3 tumors. We compared each tumor stage group with the control group using the Mann-Whitney test to verify the statistical significance of observed differences. The ROC curve built on the change in threshold cycle revealed that with this method we attained 92.68% sensitivity and 64.71% specificity (AUC 0.798, p=0.0001). CONCLUSIONS: Bradeion/SEPT4 transcript levels are significantly increased in patients with transitional cell bladder cancer compared to healthy controls. Our preliminary study supports the possible usefulness of Bradeion as a urinary marker of urothelial disease.

Intragastric balloon positioning and removal: sedation or general anesthesia?

BACKGROUND: Different anesthesiological techniques are currently used for intragastric balloon positioning and removal. The aim of this study is to compare different anesthesiological approaches for balloon positioning and removal in a large multicentric patient population. METHODS: Retrospective multicenter study was conducted. From May 2000 to April 2008, 3,824 patients underwent BIB(®) placement [1,022 male/2,802 female; mean age 39.5 ± 14.7 years, range 12-71 years; mean body mass index (BMI) 44.8 ± 9.7 kg/m(2), range 28.0-79.1 kg/m(2); excess weight (EW) 59.1 ± 29.8 kg, range 16-210 kg; %EW 89.3 ± 31.7, range 21.4-262]. Patients were allocated to three groups according to anesthesiological technique used: conscious sedation (group A), deep sedation (group B), and general anesthesia (group C). Intragastric balloon was placed after diagnostic endoscopy and removed after 6 months. Both positioning and removal were done under different protocols. Conscious sedation was obtained with topical lidocaine spray, adding diazepam (0.05-0.1 mg/kg iv) or midazolam (0.03-0.05 mg/kg iv). Deep sedation was obtained with propofol alone or adding other drugs such as midazolam, meperidine/fentanyl or meperidine/fentanyl + midazolam. General anesthesia was obtained with midazolam premedication (0.01-0.02 mg/kg iv) followed by induction with propofol (1-1.5 mg/kg iv) + Norcuron (80 mcg/kg iv) + fentanyl (0.5-1 mcg/kg iv), and maintenance with propofol (50-150 µg/kg/min) or sevorane. Oxygen saturation, hemodynamic stability, major anesthesiological complications and related mortality, patient satisfaction, time to return to autonomous walking, duration of procedure, and hospital stay were considered. RESULTS: Sedation-related mortality was absent. A significant number of patients with bronchoinhalation during balloon removal was observed with general anesthesia (P < 0.001). CONCLUSIONS: BIB positioning and removal should be performed under conscious sedation for patient safety and comfort, and technical success.

Real-Time High Frame Rate Color Flow Mapping System.

Plane wave (PW) transmission (TX) can be profitably used to improve the performance of color flow mapping (CFM) systems by increasing the autocorrelation ensemble length (EL) and/or the frame rate (FR). Although high-end scanners tend to include imaging schemes using PW TX and parallel receive beams, high frame rate (HFR) CFM has been so far experimentally implemented mostly through research platforms that transmit PWs and beamform/process the received channel data off-line. In this article, full real-time implementation of PW CFM with continuous-time clutter filtering and extended FR/EL is reported. The field-programmable gate arrays (FPGAs) and digital signal processors (DSPs) onboard the ULA-OP 256 research scanner were programmed to perform high-speed parallel beamforming and autocorrelation-based CFM processing, respectively. Different strategies were tested, in which the TX of PWs for CFM is either continuous or interleaved with the TX of packets of B-mode pulses. A fourth-order Chebyshev continuous-time high-pass filter with programmable cutoff frequency was implemented and its clutter rejection performance was positively compared with that obtained when operating on packet data. CFM FRs up to 575 were obtained. The possibility of programming the autocorrelation EL up to 64 permitted to detect flow with high sensitivity and accuracy (average relative errors down to 0.4% ± 8.4%). In vivo HFR movies are presented, showing the dynamics of flow in the common carotid artery, which highlight the presence of secondary flow components.

Architecture for an Ultrasound Advanced Open Platform With an Arbitrary Number of Independent Channels.

Ultrasound open platforms are programmable and flexible tools for the development and test of novel methods. In most cases, they embed the electronics for the independent control of (maximum) 256 probe elements. However, a higher number of channels is needed for the control of 2-D array probes. This paper presents a system architecture that, through the hardware and software synchronization of multiple ULA-OP 256 scanners, may implement advanced open platforms with an arbitrary number of channels. The proposed solution needs a single personal computer, maintains real-time features, and preserves portability. A prototype demonstrator, composed of two ULA-OP 256 scanners connected to 512 elements of a matrix array, was implemented and tested according to different channel configurations. Experiments performed under MATLAB control confirmed that by doubling the number of elements (from 256 to 512) the signal-to-noise and contrast ratios improve by 9 dB and 3 dB, respectively. Furthermore, as a full 512-channel scanner, the demonstrator can produce real-time B-mode images at 18 Hz, high enough for probe positioning during acquisitions. Also, the demonstrator permitted the implementation of a new high frame rate, bi-plane, triplex modality. All probe elements are excited to simultaneously produce two planar, perpendicular diverging waves. Each scanner independently processes the echoes received by the 256 connected elements to beamform 1300 frames per second. For each insonified plane, good quality morphological (B-mode), qualitative (color flow-), and quantitative (spectral-) Doppler images are finally shown in real-time by a dedicated interface.

Experimental and simulation study of harmonic components generated by plane and focused waves.

Although there is increasing interest in the use of plane waves (PW) in high-frame-rate imaging, not much experimental data is available about their behavior in terms of nonlinear propagation. This paper presents a detailed study of fundamental and harmonic components of the ultrasound beam associated to PW transmission from a linear array. Simulations and hydrophone measurements of PW propagation in water were performed and compared to the results obtained for focused waves (FWs) at various levels of peak negative pressure (PNP). Experimental results confirm that, at comparable PNP, the amplitudes of the harmonics reached by PWs are always higher, over extended regions, than those achieved with FW. For example, at MI = 0.2 the PW second harmonic turns out to be 9 dB higher at 25 mm depth (i.e. in the focal region), and 20 dB higher at 40 mm depth. Simulations additionally show that when ultrasound waves propagate through blood or muscle, the situation is in general reversed but, at low MI, the second harmonic amplitude can still be higher in PW than in FW. Furthermore, it is shown that increasing the array aperture size yields higher harmonic growth in PW compared to FW.