Multimode, Aperiodic Terahertz Surface-Emitting Laser Resonators

Quasi-crystal structures are conventionally built following deterministic generation rules although they do not present a full spatial periodicity. If used as laser resonators, they open up intriguing design possibilities that are simply not possible in conventional periodic photonic crystals: the distinction between symmetric (vertically radiative but low quality factor Q) and anti-symmetric (non-radiative, high Q) modes is indeed here fully overcome, offering a concrete perspective of highly efficient vertical emitting resonators. We here exploit electrically pumped terahertz quantum cascade heterostructures to devise two-dimensional seven-fold quasi-crystal resonators, exploiting rotational order or irregularly distributed defects. By lithographically tuning the lattice quasi-periodicity and/or the hole radius of the imprinted patterns, efficient multimode surface emission with a rich sequence of spectral lines distributed over a 2.9–3.4 THz bandwidth was reached. We demonstrated multicolor emission with 67 mW of peak optical power, slope efficiencies up to ≈70 mW/A, 0.14% wall plug efficiencies and beam profile results of the rich quasi-crystal Fourier spectrum that, in the case of larger rotational order, can reach very low divergence

Multiparametric Whole Blood Dissection: A one-shot comprehensive picture of the human hematopoietic system

Human hematopoiesis is a complex and dynamic system where morphologically and functionally diverse mature cell types are generated and maintained throughout life by bone marrow (BM) Hematopoietic Stem/Progenitor Cells (HSPC). Congenital and acquired hematopoietic disorders are often diagnosed through the detection of aberrant frequency or composition of hematopoietic cell populations. We here describe a novel protocol, called “Whole Blood Dissection” (WBD), capable of analyzing in a single test‐tube, hematopoietic progenitors and all major mature cell lineages composing either BM or peripheral blood (PB) through a multiparametric flow‐cytometry analysis. WBD allows unambiguously identifying in the same tube up to 23 different blood cell types including HSPC subtypes and all the major myeloid and lymphoid lineage compartments at different stages of maturation, through a combination of 17 surface and 1 viability cell markers. We assessed the efficacy of WBD by analyzing BM and PB samples from adult (n = 8) and pediatric (n = 9) healthy donors highlighting age‐related shift in cell composition. We also tested the capability of WBD on detecting aberrant hematopoietic cell composition in clinical samples of patients with primary immunodeficiency or leukemia unveiling expected and novel hematopoietic unbalances. Overall, WBD allows unambiguously identifying >99% of the cell subpopulations composing a blood sample in a reproducible, standardized, cost‐, and time‐efficient manner. This tool has a wide range of potential pre‐clinical and clinical applications going from the characterization of hematopoietic disorders to the monitoring of hematopoietic reconstitution in patients after transplant or gene therapy

Antitumoral efficacy of the protease inhibitor gabexate mesilate in colon cancer cells harbouring KRAS, BRAF and PIK3CA mutations

The employment of anti-epidermal growth factor receptor (EGFR) antibodies represents a backbone of the therapeutic options for the treatment of metastatic colorectal cancer (mCRC). However, this therapy is poorly effective or ineffective in unselected patients. Mutations in KRAS, BRAF and PIK3CA genes have recently emerged as the best predictive factors of low/absent response to EGFR-targeted therapy. Due to the need for efficacious treatment options for mCRC patients bearing these mutations, in this short report we examined the antitumoral activity of the protease inhibitor gabexate mesilate, alone and in combination with the anti-EGFR monoclonal antibody cetuximab, in a panel of human CRC cell lines harbouring a different expression pattern of wild-type/mutated KRAS, BRAF and PIK3CA genes. Results obtained showed that gabexate mesilate significantly inhibited the growth, invasive potential and tumour-induced angiogenesis in all the CRC cells employed in this study (including those ones harbouring dual KRAS/PIK3CA or BRAF/PIK3CA mutation), while cetuximab affected these parameters only in CRC cells with KRAS, BRAF and PIK3CA wild-type. Notably, the antitumoral efficacy of gabexate mesilate and cetuximab in combination was found to be not superior than that observed with gabexate mesilate as single agent. Overall, these preliminary findings suggest that gabexate mesilate could represent a promising therapeutic option for mCRC patients, particularly for those harbouring KRAS, BRAF and PIK3CA mutations, either as monotherapy or in addition to standard chemotherapy regimens. Further studies to better elucidate gabexate mesilate mechanism of action in CRC cells are therefore warranted

Continuous-wave highly-efficient low-divergence terahertz wire lasers.

Terahertz (THz) quantum cascade lasers (QCLs) have undergone rapid development since their demonstration, showing high power, broad-tunability, quantum-limited linewidth, and ultra-broadband gain. Typically, to address applications needs, continuous-wave (CW) operation, low-divergent beam profiles and fine spectral control of the emitted radiation, are required. This, however, is very difficult to achieve in practice. Lithographic patterning has been extensively used to this purpose (via distributed feedback (DFB), photonic crystals or microcavities), to optimize either the beam divergence or the emission frequency, or, both of them simultaneously, in third-order DFBs, via a demanding fabrication procedure that precisely constrains the mode index to 3. Here, we demonstrate wire DFB THz QCLs, in which feedback is provided by a sinusoidal corrugation of the cavity, defining the frequency, while light extraction is ensured by an array of surface holes. This new architecture, extendable to a broad range of far-infrared frequencies, has led to the achievement of low-divergent beams (10°), single-mode emission, high slope efficiencies (250 mW/A), and stable CW operation

Therapeutic Drug Monitoring of Imatinib in Gist Patients

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Feasibility and efficacy of 223Ra-dichloride (223Ra) to treat bone metastases in patients (pts) with castration resistant prostate cancer (mCRPC)

Aim: To share the Tuscany single-centre experience about the employing of the novel therapeutic radiopharmaceutical 223Ra in the treatment planning of mCRPC pts

Clonal expansion of T memory stem cells determines early anti-leukemic responses and long-term CAR T cell persistence in patients

Low-affinity CD19 chimeric antigen receptor (CAR) T cells display enhanced expansion and persistence, enabling fate tracking through integration site analysis. Here we show that integration sites from early (1 month) and late (>3 yr) timepoints cluster separately, suggesting different clonal contribution to early responses and prolonged anti-leukemic surveillance. CAR T central and effector memory cells in patients with long-term persistence remained highly polyclonal, whereas diversity dropped rapidly in patients with limited CAR T persistence. Analysis of shared integrants between the CAR T cell product and post-infusion demonstrated that, despite their low frequency, T memory stem cell clones in the product contributed substantially to the circulating CAR T cell pools, during both early expansion and long-term persistence. Our data may help identify patients at risk of early loss of CAR T cells and highlight the critical role of T memory stem cells both in mediating early anti-leukemic responses and in long-term surveillance by CAR T cells

Terahertz Near-field Nanoscopy Based on Self-mixing Interferometry with Quantum Cascade Resonators

Near-field imaging techniques at terahertz frequencies (0.5-10 THz), conventionally rely on bulky laser sources and detectors. Here, we devise a compact configuration for scattering near-field nanoscopy based on quantum cascade lasers (QCL) that can simultaneously act as powerful THz source and phase-sensitive detector, exploiting optical feedback interferometry [1] , (see Fig 1a ). Self-detection is based on the reinjection of the field scattered by the AFM tip into the laser cavity causing coherent interference. The near-field scattering is measured through the induced changes in the contact voltage of the QCL. By changing the path length with a movable mirror, self-mixing interference fringes are acquired and allow to retrieve both the amplitude and phase of the scattered field giving access to the complex-valued dielectric response of the sample [2]. Interestingly for imaging applications, this detection approach is fundamentally limited only by electron transport in the QCL allowing for fast image acquisition

Effects of L-carnitine administration on left ventricular remodeling after acute anterior myocardial infarction: The L-carnitine Ecocardiografia Digitalizzata Infarto Miocardico (CEDIM) trial

Objectives. This study was performed to evaluate the effects of l-carnitine administration on long-term left ventricular dilation in patients with acute anterior myocardial infarction. Background. Carnitine is a physiologic compound that performs an essential role in myocardial energy production at the mitochondrial level. Myocardial carnitine deprivation occurs during ischemia, acute myocardial infarction and cardiac failure. Experimental studies have suggested that exogenous carnitine administration during these events has a beneficial effect on function. Methods. The l-Carnitine Ecocardiografia Digitalizzata Infarto Miocardico (CEDIM) trial was a randomized, double-blind, placebo-controlled, multicenter trial in which 472 patients with a first acute myocardial infarction and high quality two-dimensional echocardiograms received either placebo (239 patients) or l-carnitine (233 patients) within 24 h of onset of chest pain. Placebo or l-carnitine was given at a dose of 9 g/day intravenously for the first 5 days and then 6 g/day orally for the next 12 months. Left ventricular volumes and ejection fraction were evaluated on admission, at discharge from hospital and at 3, 6 and 12 months after acute myocardial infarction. Results. A significant attenuation of left ventricular dilation in the first year after acute myocardial infarction was observed in patients treated with l-carnitine compared with those receiving placebo. The percent increase in both end-diastolic and endsystolic volumes from admission to 3-, 6- and 12-mouth evaluation was significantly reduced in the l-carnitine group. No significant differences were observed in left ventricular ejection fraction changes over time in the two groups. Although not designed to demonstrate differences in clinical end points, the combined incidence of death and congestive heart failure after discharge was 14 (6%) in the l-carnitine treatment group versus 23 (9.6%) in the placebo group (p = NS). Incidence of ischemic events during follow-up was similar in the two groups of patients. Conclusions. l-Carnitine treatment initiated early after acute myocardial infarction and continued for 12 months can attenuate left ventricular dilation during the first year after an acute myocardial infarction, resulting in smaller left ventricular volumes at 3, 6 and 12 months after the emergent event

Long-term lymphoid progenitors independently sustain naïve T and NK cell production in humans.

Our mathematical model of integration site data in clinical gene therapy supported the existence of long-term lymphoid progenitors capable of surviving independently from hematopoietic stem cells. To date, no experimental setting has been available to validate this prediction. We here report evidence of a population of lymphoid progenitors capable of independently maintaining T and NK cell production for 15 years in humans. The gene therapy patients of this study lack vector-positive myeloid/B cells indicating absence of engineered stem cells but retain gene marking in both T and NK. Decades after treatment, we can still detect and analyse transduced naïve T cells whose production is likely maintained by a population of long-term lymphoid progenitors. By tracking insertional clonal markers overtime, we suggest that these progenitors can support both T and NK cell production. Identification of these long-term lymphoid progenitors could be utilised for the development of next generation gene- and cancer-immunotherapies