Synthesis and automated fluorine-18 radiolabeling of new PSMA-617 derivatives with a CuAAC radiosynthetic approach

In the last decade, the development of new radiopharmaceuticals for the imaging and therapy of prostate cancer has been a highly active and important area of research, especially focusing on the prostate-specific membrane antigen (PSMA), an antigen which is upregulated in prostate, as well as in other tumor cells. A large variety of PSMA ligands have been radiolabeled, to date. Among the various derivatives, PSMA-617 resulted to be one of the most interesting in terms of interaction with the antigen and clinical properties, and its lutetium-177 labeled version has recently been approved by regulatory agencies for therapeutic purposes. For this reasons, the radiolabeling with fluorine-18 of a PSMA-617 derivative might be of interest. Beside other methodologies to radiolabel macromolecules with fluorine-18, the “click-chemistry” approach resulted to be very useful, and the copper-catalyzed azide-alkyne cycloaddition (CuAAC) is considered one of most efficient and reliable. This paper proposes the synthesis of a suitable precursor for the radiolabeling with fluorine-18 of a new PSMA-617 derivative. The whole radiosynthetic procedure has been fully automated, and the final product, which proved to be stable in plasma, has been obtained with radiochemical yield and purity suitable for subsequent preclinical studies.     

The yield of monitoring adenovirus in pediatric hematopoietic stem cell transplant patients

Human adenovirus (HAdV) is recognized as a serious pathogen after allogeneic hematopoietic stem cell transplantation (HSCT), causing morbidity and mortality. Currently, there is no universal agreement regarding routine HAdV surveillance after HSCT. We assessed the impact of HAdV weekly monitoring by polymerase chain reaction (PCR) on HAdV viremia rates and the risk factors that influence survival. Three-hundred and fifty-six pediatric allogeneic HSCT were done between 2007 and 2015. Until July 2011, HAdV testing was performed based on clinical suspicion (cohort 1, n?=?175) and from August 2011, weekly blood-HAdV monitoring was done (cohort 2, n?=?181) until day +100. Twenty-three patients (4 [2.3%] from cohort 1 and 19 [10.5%] from cohort 2, p?=?.001) were found with HAdV viremia and seven of them died. Both cohorts had a similar incidence of HAdV-associated mortality (3/175; 1.7% in cohort 1 and 4/181; 2.2% in cohort 2). Respiratory failure was the cause of death in all patients. Clinical symptoms appeared prior to or within 5?days of HAdV detection in cohort 2. In summary, weekly monitoring was associated with higher detection of HAdV. The study could not assess survival benefit due to small numbers of HAdV-positive cases. In many instances, symptoms occurred with the development of positive HAdV blood PCR results and hence, symptomatology could have triggered the test. Future studies are needed to provide data that help establishing a uniform approach for regular monitoring of HAdV post-transplant.     

Somatic mutations activating Wiskott–Aldrich syndrome protein concomitant with RAS pathway mutations in juvenile myelomonocytic leukemia patients

The WAS gene product is expressed exclusively in the cytoplasm of hematopoietic cells and constitutional genetic abrogation of WASP leads to Wiskott–Aldrich syndrome (WAS). Moreover, mutational activation of WASP has been associated with X‐linked neutropenia. Although studies reported that patients with constitutional WAS mutations affecting functional WASP expression may present juvenile myelomonocytic leukemia (JMML)‐like features, confounding differential diagnosis above all in the copresence of mutated RAS, an activating somatic mutation of WASP has not been previously described in JMML patients. In our ongoing studies on JMML genomics, we at first detected a somatic WAS mutation in a major clone found at two consecutive relapses in one of two twins with JMML. Both twins were treated with hematopoietic stem cell transplantation after diagnosis of JMML. The somatic WAS mutation detected here displayed an activating WASP phenotype. Screening of 46 sporadic JMML patients at disease onset for mutations in the same PBD domain of WAS revealed two additional singleton patients carrying minor mutated clones. This is the first study to associate somatically acquired WASP mutations with a hematopoietic malignancy and increases insight in the complexity of the genomic landscape of JMML that shows low recurrent mutations concomitant with general hyperactivation of RAS pathway signaling.     

Penetration depth of light re-emitted by a diffusive medium: theoretical and experimental investigation

The depth at which photons penetrate into a diffusive medium before being re-emitted has been investigated with reference to a semi-infinite homogeneous medium illuminated by a pencil beam. By using the diffusion equation analytical expressions have been obtained for the probability that photons penetrate at a certain depth before being detected, and for the mean path length they travel inside each layer of the medium. Expressions have been obtained both for the cw and the time domain, and simple approximate scaling relationships describing the dependence on the scattering properties of the medium have been found. For time-resolved measurements both the probability and the mean path length are expected to be independent of the distance from the light beam at which the detector is placed and of the absorption coefficient of the medium. The penetration depth increases as the time of flight increases. In contrast, for cw measurements both the probability and the mean path length strongly depend on the distance and absorption. The penetration depth increases as the distance increases or absorption decreases. The accuracy of the analytical expressions has been demonstrated by comparisons with cw experimental results. The penetration depth and the mean path length provide useful information, for instance, for measurements of tissue oxygenation and for functional imaging of muscle and brain. In particular, the depth reached by received photons provides overall information on the volume of the tissue actually investigated, while the mean path is strictly related to the sensitivity to local variations of absorption.     

Does Restless Legs Syndrome increase cardiovascular risk in Attention-Deficit/Hyperactivity Disorder?

Preliminary evidence suggests a possible association between Attention-Deficit/Hyperactivity Disorder and Restless Legs Syndrome with or without Periodic Limb Movements during Sleep. When comorbid, Restless Legs Syndrome/Periodic Limb Movements during Sleep might aggravate Attention-Deficit/Hyperactivity Disorder symptoms. Pharmacological treatment of Attention-Deficit/Hyperactivity Disorder may be associated, at least in some cases, with adverse cardiovascular events, including clinically significant elevation in heart rate and systemic blood pressure. However, the characteristics of patients with Attention-Deficit/Hyperactivity Disorder at risk for cardiovascular events during pharmacological treatment are poorly understood. Here, we hypothesize that Restless Legs Syndrome and/or Periodic Limb Movements during Sleep comorbid with Attention-Deficit/Hyperactivity Disorder increase cardiovascular risk via imbalance in activity of the autonomic nervous system. Such an imbalance of the could be related to alterations of sleep microarchitecture also detected by cyclic alternating pattern analysis. If empirical studies confirm our hypothesis, the clinician would be advised to systematically screen for and effectively treat Restless Legs Syndrome/Periodic Limb Movements during Sleep even before starting treatment with Attention-Deficit/Hyperactivity Disorder drugs. The management of Restless Legs Syndrome/Periodic Limb Movements during Sleep might reduce cardiovascular risk during pharmacological treatment of Attention-Deficit/Hyperactivity Disorder.     

Immunological Basis for IgE Hyper-Production in Enfuvirtide-Treated HIV- Positive Patients

We previously reported that enfuvirtide (ENF) treatment is accompanied by a selective increase of serum IgE. We asked whether ENF had intrinsic capability to direct B-lymphocytes to switch to IgE and/or if it could drive CD4 T cells to a Th2 phenotype. ENF was added in vitro: (a) to B-lymphocytes stimulated with IgE-switch inducing stimuli; (b) to peripheral blood mononuclear cells. Total IgE production by B cells and IL4 and IFN-γ production by CD4 T lymphocytes were evaluated, respectively. ENF had no measurable effect on the IgE production by B-lymphocytes. In contrast, it sharply increased the IL4 to IFN-γ (a correlate of the Th2 phenotype) when added in vitro to T cells from healthy donors or from single ENF-treated patients. The hyper-IgE production in ENF-treated patients is associated with the in vitro induction of a type-2 phenotype in CD4 T cells.