Time-domain diffuse optics with 8.6 mm2 fast-gated SiPM for extreme light harvesting.

Fast time-gated single-photon detectors demonstrated high depth sensitivity in the detection of localized absorption perturbations inside scattering media, but their use for in vivo clinical applications-such as functional imaging of brain activation-was impaired by their small (<0.04mm2) active area. Here, we demonstrate, both on phantoms and in vivo, the performance of a fast-gated digital silicon photomultiplier (SiPM) that features an overall active area of 8.6mm2, overcoming the photon collection capability of established time-gated single-pixel detectors by orders of magnitude, enabling deep investigations within scattering media and high signal-to-noise ratios at late photon arrival times.

Hong-Ou-Mandel interference between independent III-V on silicon waveguide integrated lasers.

The versatility of silicon photonic integrated circuits has led to a widespread usage of this platform for quantum information-based applications, including quantum key distribution (QKD). However, the integration of simple high-repetition-rate photon sources is yet to be achieved. The use of weak-coherent pulses (WCPs) could represent a viable solution. For example, measurement device independent QKD (MDI-QKD) envisions the use of WCPs to distill a secret key immune to detector side channel attacks at large distances. Thus, the integration of III-V lasers on silicon waveguides is an interesting prospect for quantum photonics. Here we report the experimental observation of Hong-Ou-Mandel interference with 46±2% visibility between WCPs generated by two independent III-V on silicon waveguide integrated lasers. This quantum interference effect is at the heart of many applications, including MDI-QKD. This Letter represents a substantial first step towards an implementation of MDI-QKD fully integrated in silicon and could be beneficial for other applications such as standard QKD and novel quantum communication protocols.

Isolated limb perfusion for the management limb threatening soft tissue sarcomas: The role of histological type on clinical outcomes.

BACKGROUND: Hyperthermic isolated limb perfusion (HILP) is an effective neoadjuvant treatment to avoid amputation in patients with locally advanced extremity soft tissue sarcomas (STS). We aimed to investigate whether STS histological type plays a role in predicting clinical outcomes. METHODS: This study reports a retrospective analysis of 125 patients with limb threatening STS (liposarcoma, n = 41; malignant peripheral nerve sheath tumor, n = 20; leiomyosarcoma, n = 20; miscellany, n = 44), who underwent HILP from 1990 through 2015 at our institution. The following endpoints were evaluated: tumor response (assessed by radiological imaging and histology), limb sparing rate, local progression-free survival (LPFS) and overall survival (OS). RESULTS: On average, overall (complete + partial) tumor response was significantly greater in patients affected with liposarcoma as compared to those with other histotypes (radiological response rate: 38/41, 92.7% vs 66/84, 78.6%, P-value: 0.048; mean histological necrosis: 83.6% vs 52.9%, P < 0.0001). Limb sparing rate was also higher among patients with liposarcoma as compared to other histotypes (39/41, 95.1% vs 62/84, 73.8%, P-value: 0.005). As regards survival, LPFS was similar across tumor types, whereas OS resulted significantly worse in patients with limb leiomyosarcoma (log-rank P-value: 0.009). CONCLUSIONS: HILP is a very effective treatment modality for limb threatening STS. In our series, liposarcoma appears to be the histological type most sensitive to HILP in terms of tumor response and thus limb sparing, which might help clinicians in the patient selection process.

Microscopic histological characteristics of soft tissue sarcomas: analysis of tissue features and electrical resistance.

Tissue electrical conductivity is correlated with tissue characteristics. In this work, some soft tissue sarcomas (STS) excised from patients have been evaluated in terms of histological characteristics (cell size and density) and electrical resistance. The electrical resistance has been measured using the ex vivo study on soft tissue tumors electrical characteristics (ESTTE) protocol proposed by the authors in order to study electrical resistance of surgical samples excised by patients in a fixed measurement setup. The measurement setup includes a voltage pulse generator (700 V, 100 µs long at 5 kHz, period 200 µs) and an electrode with 7 needles, 20 mm-long, with the same distance arranged in a fixed hexagonal geometry. In the ESTTE protocol, the same voltage pulse sequence is applied to each different tumor mass and the corresponding resistance has been evaluated from voltage and current recorded by the equipment. For each tumor mass, a histological sample of the volume treated by means of voltage pulses has been taken for histological analysis. Each mass has been studied in order to identify the sarcoma type. For each histological sample, an image at 20× or 40× of magnification was acquired. In this work, the electrical resistance measured for each tumor has been correlated with tissue characteristics like the type, size and density of cells. This work presents a preliminary study to explore possible correlations between tissue characteristics and electrical resistance of STS. These results can be helpful to adjust the pulse voltage intensity in order to improve the electrochemotherapy efficacy on some histotype of STS.

Measuring Incompatible Observables by Exploiting Sequential Weak Values.

One of the most intriguing aspects of quantum mechanics is the impossibility of measuring at the same time observables corresponding to noncommuting operators, because of quantum uncertainty. This impossibility can be partially relaxed when considering joint or sequential weak value evaluation. Indeed, weak value measurements have been a real breakthrough in the quantum measurement framework that is of the utmost interest from both a fundamental and an applicative point of view. In this Letter, we show how we realized for the first time a sequential weak value evaluation of two incompatible observables using a genuine single-photon experiment. These (sometimes anomalous) sequential weak values revealed the single-operator weak values, as well as the local correlation between them.

Experiment Investigating the Connection between Weak Values and Contextuality.

Weak value measurements have recently given rise to a great amount of interest in both the possibility of measurement amplification and the chance for further quantum mechanics foundations investigation. In particular, a question emerged about weak values being proof of the incompatibility between quantum mechanics and noncontextual hidden variables theories (NCHVTs). A test to provide a conclusive answer to this question was given by Pusey [Phys. Rev. Lett. 113, 200401 (2014)], where a theorem was derived showing the NCHVT incompatibility with the observation of anomalous weak values under specific conditions. In this Letter we realize this proposal, clearly pointing out the connection between weak values and the contextual nature of quantum mechanics.

Electrical resistance of human soft tissue sarcomas: an ex vivo study on surgical specimens.

This paper presents a study about electrical resistance, which using fixed electrode geometry could be correlated to the tissue resistivity, of different histological types of human soft tissue sarcomas measured during electroporation. The same voltage pulse sequence was applied to the tumor mass shortly after surgical resection by means of a voltage pulse generator currently used in clinical practice for electrochemotherapy that uses reversible electroporation. The voltage pulses were applied by means of a standard hexagonal electrode composed by seven, 20-mm-long equispaced needles. Irrespective of tumor size, the electrode applies electric pulses to the same volume of tissue. The resistance value was computed from the voltage and current recorded by the pulse generator, and it was correlated with the histological characteristics of the tumor tissue which was assessed by a dedicated pathologist. Some differences in resistance values, which could be correlated to a difference in tissue resistivity, were noticed according to sarcoma histotype. Lipomatous tumors (i.e., those rich in adipose tissue) displayed the highest resistance values (up to 1700 Ω), whereas in the other soft tissue sarcomas, such as those originating from muscle, nerve sheath, or fibrous tissue, the electrical resistance measured was between 40 and 110 Ω. A variability in resistance was found also within the same histotype. Among lipomatous tumors, the presence of myxoid tissue between adipocytes reduced the electrical resistance (e.g., 50-100 Ω). This work represents the first step in order to explore the difference in tissue electrical properties of STS. These results may be used to verify whether tuning electric field intensity according to the specific STS histotype could improve tissue electroporation and ultimately treatment efficacy.

In vitro gene and chromosome characterization of expanded bone marrow mesenchymal stem cells for musculo-skeletal applications.

OBJECTIVE: A number of studies have shown the role of expanded Bone Marrow-derived Mesenchymal Stem Cells in the repair and regeneration of musculo-skeletal tissues. The current European regulations define in vitro expanded cells for clinical purposes as substantially manipulated and include them in the class of Advanced-Therapy Medicinal Products to be manufactured in compliance with current Good Manufacturing Practice. Among the characteristics that such cells should display, genomic stability has recently become a major safety concern. The aim of this study is to perform a chromosomal and genetic characterization of Bone Marrow-derived Mesenchymal Stem Cells expanded in compliance with Good Manufacturing Practice for a potential clinical use in orthopaedics. MATERIALS AND METHODS: Mesenchymal Stem Cells, isolated from bone marrow, were expanded for six weeks in compliance with current Good Manufacturing Practice. DNA profiling analyses were applied to test cross-contamination absence. Genomic stability was evaluated by means of karyotyping, sequencing of TP53, p21/CDKN1A and MDM2 genes and the expression analysis of c-MYC and H-RAS oncogenes, p21/CDKN1A, TP53, p16/CDKN2A, RB1 and p27/CDKN1B tumor suppressor genes and hTERT gene. RESULTS: The DNA profiling analysis showed a unique genetic profile for each Mesenchymal Stem Cell culture, indicating the absence of cross-contamination. Karyotyping evidentiated some chromosomal abnormalities within the 10% limit set by the Cell Products Working Party review, except for one patient. In all cases, the molecular biology analyses did not revealed DNA point mutations, acquisition or changes in gene expression. hTERT levels were undetectable. CONCLUSIONS: Cultured Mesenchymal Stem Cells do not seem to be prone to malignant transformation. In fact, although some chromosomal aberrations were found, molecular biology analyses demonstrated that the expansion phase did not induce the acquisition of de novo genetic changes.

Multichannel low power time-to-digital converter card with 21 ps precision and full scale range up to 10 µs.

We present a Time-to-Digital Converter (TDC) card with a compact form factor, suitable for multichannel timing instruments or for integration into more complex systems. The TDC Card provides 10 ps timing resolution over the whole measurement range, which is selectable from 160 ns up to 10 µs, reaching 21 ps rms precision, 1.25% LSB rms differential nonlinearity, up to 3 Mconversion/s with 400 mW power consumption. The I/O edge card connector provides timing data readout through either a parallel bus or a 100 MHz serial interface and further measurement information like input signal rate and valid conversion rate (typically useful for time-correlated single-photon counting application) through an independent serial link.

Complete quantum control of exciton qubits bound to isoelectronic centres.

In recent years, impressive demonstrations related to quantum information processing have been realized. The scalability of quantum interactions between arbitrary qubits within an array remains however a significant hurdle to the practical realization of a quantum computer. Among the proposed ideas to achieve fully scalable quantum processing, the use of photons is appealing because they can mediate long-range quantum interactions and could serve as buses to build quantum networks. Quantum dots or nitrogen-vacancy centres in diamond can be coupled to light, but the former system lacks optical homogeneity while the latter suffers from a low dipole moment, rendering their large-scale interconnection challenging. Here, through the complete quantum control of exciton qubits, we demonstrate that nitrogen isoelectronic centres in GaAs combine both the uniformity and predictability of atomic defects and the dipole moment of semiconductor quantum dots. This establishes isoelectronic centres as a promising platform for quantum information processing.

Non-contact in vivo diffuse optical imaging using a time-gated scanning system.

We report on the design and first in vivo tests of a novel non-contact scanning imaging system for time-domain near-infrared spectroscopy. Our system is based on a null source-detector separation approach and utilizes polarization-selective detection and a fast-gated single-photon avalanche diode to record late photons only. The in-vivo tests included the recording of hemodynamics during arm occlusion and two brain activation tasks. Localized and non-localized changes in oxy- and deoxyhemoglobin concentration were detected for motor and cognitive tasks, respectively. The tests demonstrate the feasibility of non-contact imaging of absorption changes in deeper tissues.

Single-photon pulsed-light indirect time-of-flight 3D ranging.

"Indirect" time-of-flight is one technique to obtain depth-resolved images through active illumination that is becoming more popular in the recent years. Several methods and light timing patterns are used nowadays, aimed at improving measurement precision with smarter algorithms, while using less and less light power. Purpose of this work is to present an indirect time-of-flight imaging camera based on pulsed-light active illumination and a 32 × 32 single-photon avalanche diode array with an improved illumination timing pattern, able to increase depth resolution and to reach single-photon level sensitivity.

Metastatic malignant soft tissue myoepithelioma: a case report showing complete response after locoregional and systemic therapy.

We report on the case of a 61-year-old man with a soft tissue malignant myoepithelioma of the second toe of the right foot. After removal of the primary tumor, the patient developed in-transit metastases of the limb that we later treated with limb perfusion, using extracorporeal circulation with complete response. Following the appearance of lymph node metastases, the patient underwent inguinal, iliac and obturator lymphadenectomy. Subsequent pelvis metastases were treated with chemotherapy and radiotherapy, with complete response. Currently, after 3 years, the patient is alive and no evidence of any residual disease is apparent.

10 ps resolution, 160 ns full scale range and less than 1.5% differential non-linearity time-to-digital converter module for high performance timing measurements.

We present a compact high performance time-to-digital converter (TDC) module that provides 10 ps timing resolution, 160 ns dynamic range and a differential non-linearity better than 1.5% LSB(rms). The TDC can be operated either as a general-purpose time-interval measurement device, when receiving external START and STOP pulses, or in photon-timing mode, when employing the on-chip SPAD (single photon avalanche diode) detector for detecting photons and time-tagging them. The instrument precision is 15 ps(rms) (i.e., 36 ps(FWHM)) and in photon timing mode it is still better than 70 ps(FWHM). The USB link to the remote PC allows the easy setting of measurement parameters, the fast download of acquired data, and their visualization and storing via an user-friendly software interface. The module proves to be the best candidate for a wide variety of applications such as: fluorescence lifetime imaging, time-of-flight ranging measurements, time-resolved positron emission tomography, single-molecule spectroscopy, fluorescence correlation spectroscopy, diffuse optical tomography, optical time-domain reflectometry, quantum optics, etc.

Non-contact time-resolved diffuse reflectance imaging at null source-detector separation.

We report results of the proof-of-principle tests of a novel non-contact tissue imaging system. The system utilizes a quasi-null source-detector separation approach for time-domain near-infrared spectroscopy, taking advantage of an innovative state-of-the-art fast-gated single photon counting detector. Measurements on phantoms demonstrate the feasibility of the non-contact approach for the detection of optically absorbing perturbations buried up to a few centimeters beneath the surface of a tissue-like turbid medium. The measured depth sensitivity and spatial resolution of the new system are close to the values predicted by Monte Carlo simulations for the inhomogeneous medium and an ideal fast-gated detector, thus proving the feasibility of the non-contact approach for high density diffuse reflectance measurements on tissue. Potential applications of the system are also discussed.

Expression and functional role of adenosine receptors in regulating inflammatory responses in human synoviocytes.

BACKGROUND AND PURPOSE: Adenosine is an endogenous modulator, interacting with four G-protein coupled receptors (A(1), A(2A), A(2B) and A(3)) and acts as a potent inhibitor of inflammatory processes in several tissues. So far, the functional effects modulated by adenosine receptors on human synoviocytes have not been investigated in detail. We evaluated mRNA, the protein levels, the functional role of adenosine receptors and their pharmacological modulation in human synoviocytes. EXPERIMENTAL APPROACH: mRNA, Western blotting, saturation and competition binding experiments, cyclic AMP, p38 mitogen-activated protein kinases (MAPKs) and nuclear factor (NF)-kappaB activation, tumour necrosis factor alpha (TNF-alpha) and interleukin-8 (IL-8) release were assessed in human synoviocytes isolated from patients with osteoarthritis. KEY RESULTS: mRNA and protein for A(1), A(2A), A(2B) and A(3) adenosine receptors are expressed in human synoviocytes. Standard adenosine agonists and antagonists showed affinity values in the nanomolar range and were coupled to stimulation or inhibition of adenylyl cyclase. Activation of A(2A) and A(3) adenosine receptors inhibited p38 MAPK and NF-kappaB pathways, an effect abolished by selective adenosine antagonists. A(2A) and A(3) receptor agonists decreased TNF-alpha and IL-8 production. The phosphoinositide 3-kinase or G(s) pathways were involved in the functional responses of A(3) or A(2A) adenosine receptors. Synoviocyte A(1) and A(2B) adenosine receptors were not implicated in the inflammatory process whereas stimulation of A(2A) and A(3) adenosine receptors was closely associated with a down-regulation of the inflammatory status. CONCLUSIONS AND IMPLICATIONS: These results indicate that A(2A) and A(3) adenosine receptors may represent a potential target in therapeutic modulation of joint inflammation.

Variable phenotypic spectrum of diabetes mellitus in a family carrying a novel KCNJ11 gene mutation.

AIMS: Heterozygous activating mutations in KCNJ11, which encodes the Kir6.2 subunit of the pancreatic ATP-sensitive potassium (K(ATP)) channel, cause both permanent and transient neonatal diabetes. Identification of KCNJ11 mutations has important therapeutic implications, as many patients can replace insulin injections with sulphonylurea tablets. The aim was to determine if a KCNJ11 mutation was responsible for a dominantly inherited form of diabetes mellitus, showing variability in age at diagnosis, in an Italian family. METHODS: We sequenced KCNJ11 in members of a three-generation family with variable phenotypes of dominantly inherited diabetes mellitus. One had transient early-onset diabetes, one had impaired glucose tolerance during the second pregnancy, and two had young-onset diabetes. None of the subjects showed permanent neonatal diabetes or neurological symptoms. RESULTS: A novel heterozygous mutation (c. 679C-->G and c. 680A-->T) was identified, resulting in a GAG-->CTG (E227L) substitution in KCNJ11. Functional studies of recombinant heterozygous K(ATP) channels revealed a small reduction in channel inhibition by ATP (IC(50) of 15 micromol/l and 38 micromol/l for wild-type and heterozygous channels, respectively) and an increase in the resting K(ATP) current. This would be expected to impair insulin secretion. The results are in agreement with the mild phenotype of the patients. CONCLUSIONS: Our results broaden the spectrum of diabetes phenotypes resulting from KCNJ11 mutations. They indicate testing for KCNJ11 mutations should be considered not only for neonatal diabetes but also for other forms of dominantly inherited diabetes with later onset, especially where these are associated with a low body mass index and low birth weight.

Pharmacological characterization of P2X1 and P2X3 purinergic receptors in bovine chondrocytes.

OBJECTIVE: The aim of the present study is that of characterizing, for the first time in a quantitative way, from a biochemical, physico chemical and functional point of view P2X(1) and P2X(3) purinergic receptors in bovine chondrocytes. The affinity and the potency of typical purinergic ligands were studied through competition binding experiments and their role in modulating chondrocyte actvities was investigated by analyzing nitric oxide (NO) and prostaglandin E2 (PGE(2)) release. METHODS: Saturation, competition binding experiments, western blotting and immunohistochemistry assays on the P2X(1) and P2X(3) purinergic receptors in bovine chondrocytes were performed. Thermodynamic analysis of the P2X(1) and P2X(3) purinergic binding was studied to investigate the forces driving drug-receptor coupling. In the functional assays (NO and PGE(2) release) the potency of purinergic agonists and antagonists was evaluated. RESULTS: Bovine chondrocytes expressed P2X(1) and P2X(3) purinergic receptors and thermodynamic parameters indicated that purinergic binding is enthalpy- and entropy-driven for agonists and totally entropy-driven for antagonists. Typical purinergic agonists such as adenosine 5'-triphosphate (ATP) and alpha,beta-methyleneATP were able to increase NO and PGE(2) release. A purinergic antagonist, A317491, was able to block the stimulatory effect on functional experiments mediated by the agonists. CONCLUSIONS: These data demonstrate for the first time the presence of functional P2X(1) and P2X(3) purinergic receptors in bovine chondrocytes. Agonists and antagonists are thermodynamically discriminated and are able to modulate functional responses such as NO and PGE(2) release. These results suggest the potential role of novel purinergic antagonists in the treatment of pathophysiological diseases linked to the inflammation and involved in articular cartilage resorption.

Production and characterization of alginate microcapsules produced by a vibrational encapsulation device.

The optimization, through a Design of Experiments (DoE) approach, of a microencapsulation procedure for isolated neonatal porcine islets (NPI) is described. The applied method is based on the generation of monodisperse droplets by a vibrational nozzle. An alginate/polyornithine encapsulation procedure, developed and validated in our laboratory for almost a decade, was used to embody pancreatic islets. We analyzed different experimental parameters including frequency of vibration, amplitude of vibration, polymer pumping rate, and distance between the nozzle and the gelling bath. We produced calcium-alginate gel microbeads with excellent morphological characteristics as well as a very narrow size distribution. The automatically produced microcapsules did not alter morphology, viability and functional properties of the enveloped NPI. The optimization of this automatic procedure may provide a novel approach to obtain a large number of batches possibly suitable for large scale production of immunoisolated NPI for in vivo cell transplantation procedures in humans.

Clinical effects of direct hemoperfusion using a polymyxin-B immobilized column in solid organ transplanted patients with signs of severe sepsis and septic shock. A pilot study.

BACKGROUND: Polymyxin B (PMX-B) is a polycationic antibiotic, known to bind the lipid A portion of endotoxin, a cell wall component found exclusively in gram negative bacteria (GNB). An extracorporeal hemoperfusion device (TORAYMYXIN) has been developed: PMX is covalently bound on the surface of an insoluble carrier material so that the endotoxin can be inactivated in the blood without exerting its toxicity on the brain and kidney. The aim of this study was to clarify the efficacy, safety and clinical effects of direct hemoperfusion with an immobilized polymyxin-B fiber column (DHP-PMX) in solid organ transplanted patients with severe sepsis or septic shock. METHODS: From June 2004 to May 2005, 15 patients (10 men and 5 women), mean age 55 years old (46-65 range), underwent kidney or liver transplantation and developed severe sepsis or septic shock, as defined by the Consensus Conference of American College Physicians/Society of Critical Care Medicine (ACCP/SCCM) criteria. GNB were detected in all the patients receiving conventional treatments including antibiotic therapy, vasopressive or inotropic agents, and ventilation support. The DHP-PMX treatment was performed three times in each patient. Hemodynamic and respiratory parameters, dosage of vasopressor/inotropic drugs were assessed at baseline and after each treatment. RESULTS: No adverse events occurred. From baseline to 3rd treatment, mean arterial pressure (MAP) was increased (from 63+/-5 to 83+/-4 mmHg), while the dosage of dobutamine (from 7.5+/-3 to 3+/-2 mcg/kg/min) and noradrenaline (from 1.3+/-0.45 to 0.05+/-0.02 mcg/kg/min) were reduced. The PaO2/FiO2 ratio increased (from 234+/-38.47 to 290+/-107.48 mmHg). CONCLUSION: The use of DHP-PMX in association with conventional therapy may be an important aid in patients with sepsis.