Prognostic Potential of the Panfungal Marker (1 → 3)-ß-D-Glucan in Invasive Mycoses Patients.

We analyze the prognostic potential of (1 → 3)-ß-D-glucan (BG) levels in predicting clinical outcomes in patients with invasive fungal infections, on a population undergoing 253 episodes (177 with positive and 76 with negative outcome). Using linear regression analysis, we assessed the prognostic potential of kinetically evaluated BG levels and we found an overall sensitivity and specificity of 68 and 82%, respectively. Moreover, using an interpretative algorithm based on two distinct cutoff values, we were able to predict the outcome in 84% of the studied population with a diagnostic accuracy of 82%.

Fungal infections of the central nervous system and paranasal sinuses in onco-haematologic patients. Epidemiological study reporting the diagnostic-therapeutic approach and outcome in 89 cases.

Invasive fungal infections (IFI) of the Central Nervous System (IFI-CNS) and Paranasal Sinuses (IFI-PS) are rare, life-threatening infections in haematologic patients, and their management remains a challenge despite the availability of new diagnostic techniques and novel antifungal agents. In addition, analyses of large cohorts of patients focusing on these rare IFI are still lacking. Between January 2010 and December 2016, 89 consecutive cases of Proven (53) or Probable (36) IFI-CNS (71/89) and IFI-PS (18/89) were collected in 34 haematological centres. The median age was 40 years (range 5-79); acute leukaemia was the most common underlying disease (69%) and 29% of cases received a previous allogeneic stem cell transplant. Aspergillus spp. were the most common pathogens (69%), followed by mucormycetes (22%), Cryptococcus spp. (4%) and Fusarium spp. (2%). The lung was the primary focus of fungal infection (48% of cases). The nervous system biopsy was performed in 10% of IFI-CNS, and a sinus biopsy was performed in 56% of IFI-PS (P = 0.03). The Galactomannan test on cerebrospinal fluid has been performed in 42% of IFI-CNS (30/71), and it was positive in 67%. Eighty-four pts received a first-line antifungal therapy with Amphotericine B in 58% of cases, Voriconazole in 31% and both in 11%. Moreover, 58% of patients received 2 or more lines of therapy and 38% were treated with a combination of 2 or more antifungal drugs. The median duration of antifungal therapy was 60 days (range 5-835). A surgical intervention was performed in 26% of cases but only 10% of IFI-CNS underwent neurosurgical intervention. The overall response rate to antifungal therapy (complete or partial response) was 57%, and 1-year overall survival was 32% without significant differences between IFI-CNS and IFI-PS. The overall mortality was 69% but the IFI attributable mortality was 33%. Mortality of IFI-CNS/PS remains high but, compared to previous historical data, it seems to be reduced probably due to the availability of newer antifungal drugs. The results arising from this large contemporary cohort of cases may allow a more effective diagnostic and therapeutic management of these very rare IFI complications in haematologic patients.

Evaluation of serum (1 → 3)-ß-D-glucan clinical performance: kinetic assessment, comparison with galactomannan and evaluation of confounding factors.

PURPOSE: We investigated the clinical performance of (1 → 3)-ß-D-glucan (BG), as an early marker of invasive fungal infections (IFI), in different clinical settings. METHODS: BG serum levels were assessed by Fungitell (Associates of Cape Cod, Inc), in parallel with galactomannan (GM) when requested by clinicians. By a prospective monocentric study, 270 episodes at risk or with suspect of IFI were enrolled, namely 58 proven-probable invasive aspergillosis (IA), 27 proven invasive candidiasis (IC), 11 possible IC, 16 P.jirovecii pneumonia (PJP), 4 episodes of other IFI and 154 non-IFI controls. RESULTS: We found that (a) the BG overall sensitivity, specificity, positive predictive value and negative predictive value (NPV) were 87.9, 80.5, 76.7 and 89.9 %, respectively; (b) the highest sensitivity was found in the IC groups, followed by PJP, IA and other IFI groups; (c) an association was observed between BG kinetics and patients outcome; (d) in the IA episodes, the combination of BG or GM vs GM alone increased sensitivity from 60.0 to 83.3 % in the haematological patients; (e) false-positive BG results were related to Gram-negative infections or infusion of polyclonal IgM-enriched immunoglobulins, where high levels of BG were indeed detected. CONCLUSION: Besides strengthening its overall good clinical performance, we provide evidence that serum BG correlates with clinical outcome and that, once used in combination with GM, BG allows to enhance IFI diagnosis rate. The high sensitivity and NPV, observed in the Intensive Care Unit setting, open to BG validation as a marker for assessment of antifungal treatment.

Clinical performance of a commercial real-time PCR assay for Aspergillus DNA detection in serum samples from high-risk patients: comparison with a galactomannan enzyme immunoassay.

We investigated the clinical performance of a polymerase chain reaction (PCR)-based commercial platform, the Myconostica MycAssay™ Aspergillus (MAP), for fungal DNA detection in the serum of patients at risk of invasive aspergillosis (IA). Sixty-four hospitalized patients were prospectively enrolled and a total of 71 different episodes were investigated (30 episodes were clinically/microbiologically classified as IA and 41 as control episodes). When MAP was compared to the galactomannan (GM) assay, no significant differences were found in terms of sensitivity (46.7% vs. 50.0%), specificity (97.6% vs. 95.1%), positive predictive value (PPV) (93.3% vs. 88.2%), and negative predictive value (NPV) (71.4% vs. 72.2%). The corresponding areas under the curve (AUC) of the receiver operating characteristic (ROC) curves were also superimposable. Overall, because of the good agreement between the two assays and considering the high specificity and PPV of the MAP, we suggest the use of this PCR-based platform as a second-level examination for the evaluation of clinically undefined cases where culture or GM have provided positive results.

Feedbacks and adaptive capabilities of the PI3K/Akt/mTOR axis in acute myeloid leukemia revealed by pathway selective inhibition and phosphoproteome analysis.

Acute myeloid leukemia (AML) primary cells express high levels of phosphorylated Akt, a master regulator of cellular functions regarded as a promising drug target. By means of reverse phase protein arrays, we examined the response of 80 samples of primary cells from AML patients to selective inhibitors of the phosphatidylinositol 3 kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) axis. We confirm that >60% of the samples analyzed are characterized by high pathway phosphorylation. Unexpectedly, however, we show here that targeting Akt and mTOR with the specific inhibitors Akti 1/2 and Torin1, alone or in combination, result in paradoxical Akt phosphorylation and activation of downstream signaling in 70% of the samples. Indeed, we demonstrate that cropping Akt or mTOR activity can stabilize the Akt/mTOR downstream effectors Forkhead box O and insulin receptor substrate-1, which in turn potentiate signaling through upregulation of the expression/phosphorylation of selected growth factor receptor tyrosine kinases (RTKs). Activation of RTKs in turn reactivates PI3K and downstream signaling, thus overruling the action of the drugs. We finally demonstrate that dual inhibition of Akt and RTKs displays strong synergistic cytotoxic effects in AML cells and downmodulates Akt signaling to a much greater extent than either drug alone, and should therefore be explored in AML clinical setting.

Compatibility between coherent reflective burst-mode PON and TWDM-PON physical layers.

We discuss the compatibility between reflective PON architectures and the recently defined ITU-T G.989.1 TWDM-PON. Focusing on the upstream, we experimentally demonstrate that, by using burst-mode coherent detection at OLT, reflective PON can achieve the specification target set for TWDM-PON, without requiring precise wavelength accuracy at ONU. Compared to the companion ECOC 2013 paper, we investigate on the differential optical path loss (DOPL) issue, proposing a simple SOA gain control algorithm to achieve reliable transmission for DOPL up to 17 dB.

1306-km 20x124.8-Gb/s PM-64QAM transmission over PSCF with net SEDP 11,300 (b ∙ km)/s/Hz using 1.15 samp/symb DAC.

We demonstrated the transmission of a Nyquist-WDM signal based on PM-64QAM modulation in an EDFA-only submarine configuration composed of 54.4 km-long fiber spans: 20 channels at 124.8-Gb/s were propagated over 1306 km of low-loss pure-silica-core fiber (PSCF). Thanks to an aggressive digital spectral shaping, we achieved a raw spectral efficiency (SE) of 10.4 b/s/Hz, corresponding to 8.67 b/s/Hz net SE when considering a 20% FEC overhead. Transmitter DACs are operated at a record-low 1.15 samples/symbol, enabled by the insertion of advanced anti-alias filters. The achieved SE-times-distance product was 11,327 (b ∙ km)/(s ∙ Hz), the highest reported so far for PM-64QAM. Combining the experimental results with the performance predictions obtained using an analytical model of nonlinear propagation in uncompensated coherent optical systems (the so-called "GN-model"), we show that PM-64QAM is a realistic option for ultra-high capacity systems in the 1,000 km range, carrying up 40 Tb/s in the C-band.

Characterization of uncooled RSOA for upstream transmission in WDM reflective PONs.

We investigate on the uncooled RSOA driving parameters in WDM reflective PONs, focusing on an upstream path at 1.25 Gbit/s using pure binary modulation. We show how the optimal values change using direct-detection or self-coherent receivers. In particular, for the latter, the driving point optimization allows a gain of more than 3 dB in terms of ODN loss compared to a standard On-Off Keying, generating a quasi-PSK modulation. We also address operating temperature and wavelength dependence issues.

Optimization of self-coherent reflective PON to achieve a new record 42 dB ODN power budget after 100 km at 1.25 Gbps.

We demonstrate a greater than 42 dB optical distribution network power budget in the upstream of a 1.25 Gbps self-coherent reflective PON after 100 km of installed fibers, using off-the-shelf optoelectronic components, improving our previous result by 4 dB. We discuss all system optimizations introduced in the setup in order to reach such a result, including 8B/10B high-pass filtering and Faraday rotation at the ONU.

ß-HHVs and HHV-8 in Lymphoproliferative Disorders.

Similarly to Epstein-Barr virus (EBV), the human herpesvirus-8 (HHV-8) is a γ-herpesvirus, recently recognized to be associated with the occurrence of rare B cell lymphomas and atypical lymphoproliferations, especially in the human immunodeficiency virus (HIV) infected subjects. Moreover, the human herpesvirus-6 (HHV-6), a ß-herpesvirus, has been shown to be implicated in some non-malignant lymph node proliferations, such as the Rosai Dorfman disease, and in a proportion of Hodgkin's lymphoma cases. HHV-6 has a wide cellular tropism and it might play a role in the pathogenesis of a wide variety of human diseases, but given its ubiquity, disease associations are difficult to prove and its role in hematological malignancies is still controversial. The involvement of another ß-herpesvirus, the human cytomegalovirus (HCMV), has not yet been proven in human cancer, even though recent findings have suggested its potential role in the development of CD4(+) large granular lymphocyte (LGL) lymphocytosis. Here, we review the current knowledge on the pathogenetic role of HHV-8 and human ß-herpesviruses in human lymphoproliferative disorders.

Analytical results on channel capacity in uncompensated optical links with coherent detection.

Based on a recently introduced model of non-linear propagation, we propose analytical formulas for the capacity limit of polarization-multiplexed ultra-dense WDM uncompensated coherent optical systems at the Nyquist limit, assuming both lumped and ideally distributed amplification. According to these formulas, capacity fundamentally depends on the transmitted power spectral density and on the total optical WDM bandwidth, whereas it does not depend on symbol-rate. Also, capacity approximately decreases by 2 [bit/s/Hz] for every doubling of link length. We show examples of capacity calculations for specific ultra-long-haul links with different polarization-multiplexed (PM) constellations, i.e. ideal PM-Gaussian, PM-QPSK (quadrature-phase shift keying) and PM-QAM (quadrature amplitude modulation). We show that the launch power maximizing capacity is independent of link length and modulation format. We also discuss the usable range of PM-QAM systems and validate analysis with simulations.

Experimental validation of an analytical model for nonlinear propagation in uncompensated optical links.

Link design for optical communication systems requires accurate modeling of nonlinear propagation in fibers. This topic has been widely analyzed in last decades with partial successes in special conditions, but without a comprehensive solution. Since the introduction of coherent detection with electronic signal processing the scenario completely changed because this category of systems shows better performances in links without in-line dispersion management. This change to uncompensated transmission allowed to modify the approach in the study of nonlinear fiber propagation and in recent years a series of promising analytical models have been proposed. In this paper, we present an experimental validation over different fiber types of an analytical model for nonlinear propagation over uncompensated optical transmission links. Considering an ultra-dense WDM system, we transmitted ten 120-Gb/s PM-QPSK signals over a multi-span system probing different fiber types: SSMF, PSCF and NZDSF. A good matching was found in all cases showing the potential of the analytical model for accurate performance estimation that could lead to powerful tools for link design.

Performance evaluation of coherent WDM PS-QPSK (HEXA) accounting for non-linear fiber propagation effects.

Coherent-detection (CoD) permits to fully exploit the four-dimensional (4D) signal space consisting of the in-phase and quadrature components of the two fiber polarizations. A well-known and successful format exploiting such 4D space is Polarization-multiplexed QPSK (PM-QPSK). Recently, new signal constellations specifically designed and optimized in 4D space have been proposed, among which polarization-switched QPSK (PS-QPSK), consisting of a 8-point constellation at the vertices of a 4D polychoron called hexadecachoron. We call it HEXA because of its geometrical features and to avoid acronym mix-up with PM-QPSK, as well as with other similar acronyms. In this paper we investigate the performance of HEXA in direct comparison with PM-QPSK, addressing non-linear propagation over realistic links made up of 20 spans of either standard single mode fiber (SSMF) or non-zero dispersion-shifted fiber (NZDSF). We show that HEXA not only confirms its theoretical sensitivity advantage over PM-QPSK in back-to-back, but also shows a greater resilience to non-linear effects, allowing for substantially increased span loss margins. As a consequence, HEXA appears as an interesting option for dual-format transceivers capable to switch on-the-fly between PM-QPSK and HEXA when channel propagation degrades. It also appears as a possible direct competitor of PM-QPSK, especially over NZDSF fiber and uncompensated links.

Evaluation of the computational effort for chromatic dispersion compensation in coherent optical PM-OFDM and PM-QAM systems.

Recently, coherent-detection (CoD) polarization multiplexed (PM) transmission has attracted considerable interest, specifically as a possible solution for next-generation systems transmitting 100 Gb/s per channel and beyond. In this context, enabled by progress in ultra-fast digital signal processing (DSP) electronics, both multilevel phase/amplitude modulated formats (such as QAM) and orthogonal-frequency-division multiplexed (OFDM) formats have been proposed. One specific feature of DSP-supported CoD is the possibility of dealing with fiber chromatic dispersion (CD) electronically, either by post-filtering (PM-QAM) or by appropriately introducing symbol-duration redundancy (PM-OFDM). In both cases, ultra-long-haul fully uncompensated links seem to be possible. In this paper we estimate the computational effort required by CD compensation, when using the PM-QAM or PM-OFDM formats. Such effort, when expressed as number of operations per received bit, was found to be logarithmic with respect to link length, bit rate and fiber dispersion, for both classes of systems. We also found that PM-OFDM may have some advantage over PM-QAM, depending mostly on the over-sampling needed by the two systems. Asymptotically, for large channel memory and small over-sampling, the two systems tend to require the same CD-compensation computational effort. We also showed that the effort required by the mitigation of polarization-related effects can in principle be made small as compared to that of CD over long uncompensated links.