Regulatory T cells expressing CD19-targeted chimeric antigen receptor restore homeostasis in Systemic Lupus Erythematosus.

Systemic Lupus Erythematosus (SLE) is a progressive disease leading to immune-mediated tissue damage, associated with an alteration of lymphoid organs. Therapeutic strategies involving regulatory T (Treg) lymphocytes, which physiologically quench autoimmunity and support long-term immune tolerance, are considered, as conventional treatment often fails. We describe here a therapeutic strategy based on Tregs overexpressing FoxP3 and harboring anti-CD19 CAR (Fox19CAR-Tregs). Fox19CAR-Tregs efficiently suppress proliferation and activity of B cells in vitro, which are relevant for SLE pathogenesis. In an humanized mouse model of SLE, a single infusion of Fox19CAR-Tregs restricts autoantibody generation, delay lymphopenia (a key feature of SLE) and restore the human immune system composition in lymphoid organs, without detectable toxicity. Although a short survival, SLE target organs appear to be protected. In summary, Fox19CAR-Tregs can break the vicious cycle leading to autoimmunity and persistent tissue damage, representing an efficacious and safe strategy allowing restoration of homeostasis in SLE.

Activating two-dimensional semiconductors for photocatalysis: a cross-dimensional strategy.

The emerging two-dimensional (2D) semiconductors substantially extend materials bases for versatile applications such as semiconductor photocatalysis demanding semiconductive matrices and large surface areas. The dimensionality, while endowing 2D semiconductors the unique properties to host photocatalytic functionality of pollutant removal and hydrogen evolution, hurdles the activation paths to form heterogenous photocatalysts where the photochemical processes are normally superior over these on the mono-compositional counterparts. In this perspective, we present a cross-dimensional strategy to employ thenD (n= 0-2) clusters or nanomaterials as activation partners to boost the photocatalytic activities of the 2D semiconductors. The formation principles of heterogenous photocatalysts are illustrated specifically for the 2D matrices, followed by selection criteria of them among the vast 2D database. The computer investigations are illustrated in the density functional theory route and machine learning benefitted from the vast samples in the 2D library. Synthetic realizations and characterizations of the 2D heterogenous systems are introduced with an emphasis on chemical methods and advanced techniques to understand materials and mechanistic studies. The perspective outlooks cross-dimensional activation strategies of the 2D materials for other applications such as CO2removal, and materials matrices in other dimensions which may inspire incoming research within these fields.

Variability on the energy properties of charcoal and charcoal briquettes for barbecue.

In recent years there has been a strong increase in interest in the world of barbecues and outdoor cooking in high-income countries. Referring to FAO data, an exponential growth in imports of charcoal was observed in Europe and North America. Italy is one of the major European consumers and importers. On the market it is possible to find material with different characteristics and origins. However, analysis aimed at ascertaining the quality of the material are poorly performed. This research aimed to analyze the energy properties of charcoal commonly available on the Italian market. Twenty-four bags of charcoal and charcoal briquettes were analyzed. Eighteen samples represent the products most easily found on the market, in stores and on websites. In addition, six samples were supplied directly by the producer/importing company. The samples were grouped according to the continent of origin of the material (Europe, North-Central America and South America). Charcoal briquette samples were included together in a group. Referring to the ISO 17225-1 standard, the moisture content, ash content, heating value, volatile matter and fixed carbon were determined. Except for the moisture content, the results of the tests performed on all parameters show a strong variability both between different groups and within the same group. In detail, the European charcoal samples show characteristics more suitable for their use in barbecues. These have the highest values of fixed carbon and heating value and, at the same time, low values of ash and volatile matter. On the contrary, charcoal briquettes have less suitable characteristics for barbecue. The work also highlighted some gaps in the reference standard relating to laboratory analyses. To ensure careful control of the qualitative characteristics of the products on the market, it is necessary to promote the creation of a quality brand.

Case Report: Invasive Fungal Infection and Daratumumab: A Case Series and Review of Literature.

Life expectancy of multiple myeloma (MM) patients has improved in last years due to the advent of anti-CD38 monoclonal antibodies in combination with immunomodulators and proteasome inhibitors. However, morbidity and mortality related to infections remain high and represent a major concern. This paper describes the "real life" risk of invasive fungal infections (IFI) in patients treated with daratumumab-based therapy and reviews the relevant literature. In a series of 75 patients we only observed three cases of fungal pneumonia. Unfortunately, the early signs and symptoms were not specific for fungal infection. Diagnostic imaging, microbiology and patient history, especially previous therapies, are critical in the decision to start antifungal treatment. Recognising the subgroup of MM patients with high risk of IFI can increase the rate of diagnosis, adequate treatment and MM-treatment recovery.

CD3+ graft cell count influence on chronic GVHD in haploidentical allogeneic transplantation using post-transplant cyclophosphamide.

The effects of graft or donor characteristics in haploidentical hematopoietic cell transplantation (HCT) using post-transplant cyclophosphamide (PT-Cy) are largely unknown. In this multicenter retrospective study we analyzed the correlations between graft cell composition (CD34+, CD3+) and donor features on transplant outcomes in 234 patients who underwent HCT between 2010 and 2016. On multivariate analysis, the use of peripheral blood stem cells (PBSC) was associated with an increased incidence of grade 2-4 acute GVHD [HR 1.94, 95% confidence Interval (CI) = 1.01-3.98, p = 0.05]. An elevated CD3+ graft content was associated with an increased incidence of all-grade chronic GVHD [HR 1.36 (95% CI = 1.06-1.74), p = 0.01]. This effect was confirmed only for the PBSC graft group. A higher CD34+ graft content had a protective role on non-relapse mortality [HR 0.78 (95% CI = 0.62-0.96), p = 0.02] but this was confirmed only for the bone marrow (BM)-derived graft cohort. Donor characteristics did not influence any outcomes. GVHD prophylaxis should be modulated accordingly to CD3+ graft content, especially when a PBSC graft is used. These results need further validation in prospective trials.

Control of infectious mortality due to carbapenemase-producing Klebsiella pneumoniae in hematopoietic stem cell transplantation.

Carbapenemase-producing Klebsiella pneumoniae (KPC-Kp) infections are an emerging cause of death after hematopoietic stem cell transplantation (HSCT). In allogeneic transplants, mortality rate may rise up to 60%. We retrospectively evaluated 540 patients receiving a transplant from an auto- or an allogeneic source between January 2011 and October 2015. After an Institutional increase in the prevalence of KPC-Kp bloodstream infections (BSI) in June 2012, from July 2012, 366 consecutive patients received the following preventive measures: (i) weekly rectal swabs for surveillance; (ii) contact precautions in carriers (iii) early-targeted therapy in neutropenic febrile carriers. Molecular typing identified KPC-Kp clone ST512 as the main clone responsible for colonization, BSI and outbreaks. After the introduction of these preventive measures, the cumulative incidence of KPC-Kp BSI (P=0.01) and septic shocks (P=0.01) at 1 year after HSCT was significantly reduced. KPC-Kp infection-mortality dropped from 62.5% (pre-intervention) to 16.6% (post-intervention). Day 100 transplant-related mortality and KPC-Kp infection-related mortality after allogeneic HSCT were reduced from 22% to 10% (P=0.001) and from 4% to 1% (P=0.04), respectively. None of the pre-HSCT carriers was excluded from transplant. These results suggest that active surveillance, contact precautions and early-targeted therapies, may efficiently control KPC-Kp spread and related mortality even after allogeneic HSCT.

Effect of the concentration of essential oil on orange peel waste biomethanization: Preliminary batch results.

The cultivation of orange (Citrus×sinensis) and its transformation is a major industry in many countries in the world, it leads to the production of about 25-30Mt of orange peel waste (OPW) per year. Until now many options have been proposed for the management of OPW but although they are technically feasible, in many cases their economic/environmental sustainability is questionable. This paper analyse at lab scale the possibility of using OPW as a substrate for anaerobic digestion. Specific objectives are testing the possible codigestion with municipal biowaste, verifying the effect on methane production of increasingly high concentration of orange essential oil (EO, that is well known to have antioxidant properties that can slower or either inhibit biomass activity) and obtaining information on the behaviour of d-limonene, the main EO component, during anaerobic digestion. The results indicate that OPW can produce up to about 370LnCH4/kgVS in mesophilic conditions and up to about 300LnCH4/kgVS in thermophilic conditions. The presence of increasingly high concentrations of EO temporary inhibits methanogenesis, but according to the results of batch tests, methane production restarts while d-limonene is partially degraded through a pathway that requires its conversion into p-cymene as the main intermediate.

Haploidentical HSCT: a 15-year experience at San Raffaele.

Hematopoietic SCT (HSCT) from HLA haploidentical family donors is a promising therapy for high-risk hematological malignancies. In the past 15 years at San Raffaele Scientific Institute, we investigated several transplant platforms and post transplant cellular-based interventions. We showed that T cell-depleted haploidentical transplantation followed by the infusion of genetically modified donor T cells (TK007 study, Eudract-2005-003587-34) promotes fast and wide immune reconstitution and GvHD control. This approach is currently tested in a phase III multicenter randomized trial (TK008 study, NCT00914628). We targeted patients with advanced leukemia with a sirolimus-based, calcineurin inhibitor-free prophylaxis of GvHD to allow the safe infusion of unmanipulated PBSCs from haploidentical family donors (TrRaMM study, Eudract 2007-5477-54). Results of these approaches are summarized and discussed.

[Parricide, abuse and emotional processes: a review starting from some paradigmatic cases]. / Parricidio, abusi e processi emozionali: una rassegna partendo da alcuni casi paradigmatici.

The authors of this study tackle the complex subject of parricide, which is a rare and often brutal form of homicide. Parricide has a high emotional impact on public opinion and on our collective imagination, especially in light of the fact that the perpetrators are often minors.. Three striking cases of parricide, taken from various documented sources and judicial files from the "N. Fornelli" Juvenile Penal Institute (Bari, Italy), are presented here. A review of the literature on the topic has revealed differences between parricides committed by adults and those committed by minors. In the end, the complex issues underlying such an unusual crime are connected to abuses and maltreatment that minor perpetrators of parricide have suffered, especially the emotional processes that are activated.

Effects of peripheral FAAH blockade on NTG-induced hyperalgesia--evaluation of URB937 in an animal model of migraine.

BACKGROUND: Systemic nitroglycerin (NTG) activates brain nuclei involved in nociceptive transmission as well as in neuroendocrine and autonomic functions in rats. These changes are considered relevant for migraine because NTG consistently provokes spontaneous-like migraine attacks in migraineurs. Several studies have suggested a relationship between the endocannabinoid levels and pain mediation in migraine. URB937, a peripheral inhibitor of fatty acid amide hydrolase (FAAH)-the enzyme that degrades anandamide, produces analgesia in animal models of pain, but there is no information on its effects in migraine. AIM: We evaluated whether URB937 alters nociceptive responses in the animal model of migraine based on NTG administration in male rats, using the tail flick test and the plantar and orofacial formalin tests, under baseline conditions and after NTG administration. Furthermore, we investigated whether URB937 affects NTG-induced c-Fos expression in the brain. RESULTS: During the tail flick test, URB937 showed an antinociceptive effect in baseline conditions and it blocked NTG-induced hyperalgesia. URB937 also proved effective in counteracting NTG-induced hyperalgesia during both the plantar and orofacial formalin tests. Mapping of brain nuclei activated by NTG indicates that URB937 significantly reduces c-Fos expression in the nucleus trigeminalis caudalis and the locus coeruleus. CONCLUSIONS: The data suggest that URB937 is capable of changing, probably via indirect mechanisms, the functional status of central structures that are important for pain transmission in an animal model of migraine.

Incidence, risk factors and clinical outcome of leukemia relapses with loss of the mismatched HLA after partially incompatible hematopoietic stem cell transplantation.

Genomic loss of the mismatched human leukocyte antigen (HLA) is a recently described mechanism of leukemia immune escape and relapse after allogeneic hematopoietic stem cell transplantation (HSCT). Here we first evaluated its incidence, risk factors and outcome in 233 consecutive transplants from partially HLA-mismatched related and unrelated donors (MMRD and MMUD, respectively). We documented 84 relapses, 23 of which with HLA loss. All the HLA loss relapses occurred after MMRD HSCT, and 20/23 in patients with acute myeloid leukemia. Upon MMRD HSCT, HLA loss variants accounted for 33% of the relapses (23/69), occurring later than their 'classical' counterparts (median: 307 vs 88 days, P<0.0001). Active disease at HSCT increased the risk of HLA loss (hazard ratio (HR): 10.16; confidence interval (CI): 2.65-38.92; P=0.001), whereas older patient ages had a protective role (HR: 0.16; CI: 0.05-0.46; P=0.001). A weaker association with HLA loss was observed for graft T-cell dose and occurrence of chronic graft-versus-host disease. Outcome after 'classical' and HLA loss relapses was similarly poor, and second transplantation from a different donor appeared to provide a slight advantage for survival. In conclusion, HLA loss is a frequent mechanism of evasion from T-cell alloreactivity and relapse in patients with myeloid malignancies transplanted from MMRDs, warranting routine screening in this transplantation setting.

SCT for severe autoimmune diseases: consensus guidelines of the European Society for Blood and Marrow Transplantation for immune monitoring and biobanking.

Over the past 15 years, SCT has emerged as a promising treatment option for patients with severe autoimmune diseases (ADs). Mechanistic studies recently provided the proof-of-concept that restoration of immunological tolerance can be achieved by haematopoietic SCT in chronic autoimmunity through eradication of the pathologic, immunologic memory and profound reconfiguration of the immune system, that is, immune 'resetting'. Nevertheless, a number of areas remain unresolved and warrant further investigation to refine our understanding of the underlying mechanisms of action and to optimize clinical SCT protocols. Due to the low number of patients transplanted in each centre, it is essential to adequately collect and analyse biological samples in a larger cohort of patients under standardized conditions. The European society for blood and marrow transplantation Autoimmune Diseases and Immunobiology Working Parties have, therefore, undertaken a joint initiative to develop and implement guidelines for 'good laboratory practice' in relation to procurement, processing, storage and analysis of biological specimens for immune reconstitution studies in AD patients before, during and after SCT. The aim of this document is to provide practical recommendations for biobanking of samples and laboratory immune monitoring in patients with ADs undergoing SCT, both for routine supportive care purposes and investigational studies.

Metachronous elastofibromas.

Elastofibroma Dorsi (EFD) is a rare pseudo-tumor characterized by the overgrowth of elastic fibers mixed to adipose and connective tissues typically growing in the subscapular region. This can be bilateral but only rarely synchronous affecting different anatomical sites at the same time. Hereby we present a case of a 42-year-old male patient found with three different metachronous elastofibromas: bilateral EFD and a further third localization by the right elbow. The two EFs in the subscapular region were resected. After surgery pain reoccurred on the right side. This required the implantation of a spinal electro-stimulator. The elbow lesion was not excised as it was asymptomatic.

Early molecular diagnosis of aspergillosis in a patient with acute myeloid leukaemia.

Diagnosis of invasive fungal infection remains challenging. Here we report a case of early diagnosis of invasive aspergillosis in a neutropenic patient affected by acute myeloid leukaemia, achieved through the detection of Aspergillus fumigatus species-specific ribonucleic acid sequences by a sensitive multiplex real-time polymerase chain reaction-based molecular assay. Thanks to the early diagnosis, targeted therapy was promptly established and the severe fungal infection controlled, allowing the patient to subsequently receive allogeneic hematopoietic stem cell transplantation from a haploidentical donor, her only curative option. Also in this instance, targeted secondary antifungal prophylaxis with voriconazole avoided any other fungal infection afterwards. This report suggests how the implementation of molecular assays in combination with routine diagnostic procedures, can improve microbiological diagnosis in sepsis, particularly in case of fungal infection, difficult to detect with standard microbiological culture methods.

Effects of CGRP receptor antagonism in nitroglycerin-induced hyperalgesia.

BACKGROUND: The release of calcitonin gene-related peptide (CGRP) from trigeminal nerves plays a central role in the pathophysiology of migraine and clinical evidence shows an antimigraine effect for CGRP receptor antagonists. Systemic administration of nitroglycerin (NTG), a nitrovasodilator, consistently provokes spontaneous-like migraine attacks in migraine sufferers; in the rat, systemic NTG induces a condition of hyperalgesia, probably through the activation of cerebral/spinal structures involved in nociceptive transmission. AIM: The aim of this article is to test the analgesic effect of the CGRP receptor antagonist MK-8825 in two animal models of pain that may be relevant for migraine: the tail flick test and the formalin test performed during NTG-induced hyperalgesia. RESULTS: MK-8825 showed analgesic activity when administered alone at both the tail flick test and the formalin test. Furthermore, the CGRP antagonist proved effective in counteracting NTG-induced hyperalgesia in both tests. MK-8825 indeed reduced the nociceptive behavior when administered either simultaneously or prior to (30-60 minutes before) NTG. CONCLUSION: These data suggest that MK-8825 may represent a potential therapeutic tool for the treatment of migraine.