Perseverative responding and neuroanatomical alterations in adult heterozygous reeler mice are mitigated by neonatal estrogen administration

According to the "extreme-male brain" theory, elevated fetal testosterone levels may partly explain the skewed sex ratio found in Autism Spectrum Disorders (ASD). Correcting this testosterone imbalance by increasing estrogen levels may mitigate the abnormal phenotype. Accordingly, while control heterozygous reeler (rl/+) male mice - a putative model of neuroanatomical and behavioral endophenotypes in ASD - show a decreased number of Purkinje cells (PC) compared to control wild-type (+/+) littermates, neonatal estradiol administration has been shown to correct this deficit in the short-term (i.e. on postnatal day 15). Here, we further investigated the neuroanatomical and behavioral abnormalities of rl/+ male mice and the potential compensatory effects of neonatal treatment with estradiol. In a longitudinal study, we observed that: i) infant rl/+ mice showed reduced motivation for social stimuli; ii) adult rl/+ male mice showed reduced cognitive flexibility; iii) the number of amygdalar parvalbumin-positive GABAergic interneurons were remarkably reduced in rl/+ mice; iv) neonatal estradiol administration into the cisterna magna reverted the abnormal profile both at the behavioral and at the neuroanatomical level in the amygdala but did not compensate for the cerebellar abnormalities in adulthood. This study supports the view that an increased excitation-to-inhibition ratio in the cerebellum and in the amygdala during a critical window of development could be crucial to the social and cognitive phenotype of male rl/+ mice, and that acute estradiol treatment during this critical window may mitigate symptoms' severity

Iron Metabolism in the Tumor Microenvironment-Implications for Anti-Cancer Immune Response

New insights into the field of iron metabolism within the tumor microenvironment have been uncovered in recent years. Iron promotes the production of reactive oxygen species, which may either trigger ferroptosis cell death or contribute to malignant transformation. Once transformed, cancer cells divert tumor-infiltrating immune cells to satisfy their iron demand, thus affecting the tumor immunosurveillance. In this review, we highlight how the bioavailability of this metal shapes complex metabolic pathways within the tumor microenvironment and how this affects both tumor-associated macrophages and tumor-infiltrating lymphocytes functions. Furthermore, we discuss the potentials as well as the current clinical controversies surrounding the use of iron metabolism as a target for new anticancer treatments in two opposed conditions: i) the "hot" tumors, which are usually enriched in immune cells infiltration and are extremely rich in iron availability within the microenvironment, and ii) the "cold" tumors, which are often very poor in immune cells, mainly due to immune exclusion

Mutational analysis of BCORL1 in the leukemic transformation of chronic myeloproliferative neoplasms.

BCORL1 mutations do not seem to be commonly associated with leukemic transformation of MPN, further substantiating the different molecular profile compared with denovo leukemias. Although the small number of cases does not allow us to exclude that BCORL1 mutations can be found also in post-MPN AML, their occurrence is, at least, very infrequent and their detection does not appear to deserve clinical relevance

PO-032 The knock-down of ferritin heavy subunit induces xenobiotic-resistance in k562 cells through the activation of nf-kb pathway

Introduction The transcriptional factor NF-κB, composed by five subunits (RelA/p65, c-Rel, RelB, p50, p52), is largely involved in many facets of cellular physiology such as innate and adaptive immunity as well as inflammation. In addition, NF-kB play a central role in cancer cell survival and chemoresistance partly by its implication in cross-talks with redox-regulating proteins. Ferritin is the major iron storage protein; it is composed by a variable assembly of Heavy (FHC) and Light (FLC) subunits. FHC, in particular, has been widely demonstrated to be devoted in iron uptake and release thus controlling the redox homeostasis. Material and methods K562 erythroleukemia cells were stably silenced for FHC by using the shRNA method. Then FHC reconstitution was achieved by transient transfection of a FHC specific expression vector. ROS were determined by incubating cells with the redox-sensitive probe 2'−7'-DCF. NAC was used to inhibit ROS production. MTT assay was performed to analyse cell viability. Increasing concentrations of Doxorubicin, ranging from 0 to 5 µM, were used to treat K562 cells. Results and discussions The results of this study highlighted that FHC amounts negatively affect NF-kB activation in K562 cells. FHC silencing was accompanied by an increased expression of the nuclear NF-kB subunit p65, FHC rescue determined nuclear p65 decrease. FHC silencing is responsible for intracellular ROS production and ROS are implicated in NF-kB pathway. To elucidate the relationship between ROS amount and nuclear p65 content, we determined ROS amounts in our in vitro model and evaluated p65 nuclear expression after treatment with the ROS scavenger NAC. First, we observed that, as expected, ROS levels increased upon FHC silencing and return to basal levels upon NAC treatment. Interestingly, NAC was also able to decrease nuclear p65 amount in FHC-silenced K562 cells. Considering the effect of NF-kB activated pathway on cell survival, we analysed the effect of FHC silencing-mediated p65 increase in K562 cells upon treatment with increasing doses of Doxorubicin. Cell viability assay highlighted that FHC-silencing was accompanied by an increased resistance to the drug with an IC 50 about doubled compared to that of the K562 control cells at each the time points. This resistance of FHC-silenced cells was reverted upon NF-kB inhibitor transfection. Conclusion FHC silencing induced NF-kB activation in K562 cells through the modulation of intracellular ROS content. This regulatory axis can be used to modulate K562 chemoresistance

Combined lymphocyte/monocyte count, D-dimer and iron status predict COVID-19 course and outcome in a long-term care facility

Background: The Sars-CoV-2 can cause severe pneumonia with multiorgan disease; thus, the identification of clinical and laboratory predictors of the progression towards severe and fatal forms of this illness is needed. Here, we retrospectively evaluated and integrated laboratory parameters of 45 elderly subjects from a long-term care facility with Sars-CoV-2 outbreak and spread, to identify potential common patterns of systemic response able to better stratify patients’ clinical course and outcome. Methods: Baseline white blood cells, granulocytes’, lymphocytes’, and platelets’ counts, hemoglobin, total iron, ferritin, D-dimer, and interleukin-6 concentration were used to generate a principal component analysis. Statistical analysis was performed by using R statistical package version 4.0. Results: We identified 3 laboratory patterns of response, renamed as low-risk, intermediate-risk, and high-risk, strongly associated with patients’ survival (p < 0.01). D-dimer, iron status, lymphocyte/monocyte count represented the main markers discriminating high- and low-risk groups. Patients belonging to the high-risk group presented a significantly longer time to ferritin decrease (p: 0.047). Iron-to-ferritin-ratio (IFR) significantly segregated recovered and dead patients in the intermediate-risk group (p: 0.012). Conclusions: Our data suggest that a combination of few laboratory parameters, i.e. iron status, D-dimer and lymphocyte/monocyte count at admission and during the hospital stay, can predict clinical progression in COVID-19

The Epidemiology of Hypoparathyroidism in Italy: An 8-Year Register-Based Study

Hypoparathyroidism is a rare endocrine disorder, but few studies have focused on the epidemiology and hospital management of the disease and none has been performed in Italy. We investigated the prevalence of dif- ferent forms of hypoparathyroidism among hospitalized patients in Italy during an 8-year period. This study is designed as a retrospective register-based study. We retrieved data from the ‘‘Record of Hospital Discharge’’ (SDO) of the Italian Health Ministry, from the year 2006 to 2013 and analyzed the codes corresponding to hypoparathyroidism-related diagnoses. The inpatient prevalence of the disease was also calculated after excluding repeated hospitalizations. Overall, 27,692 hos- pitalization episodes for hypoparathyroidism were identi- fied during the entire period (72.2% in women and 27.8% in men; mean age 49.5 ± 22.9 years). The mean length of stay was 7.4 ± 9.8 days (25.9% of the episodes requiring less than 3 days of stay). The mean hospitalization rate for hypoparathyroidism was 5.9/100,000 inhabitants per year and there was a significant decrease during the period of 2006–2013 ( p \ 0.0001). The mean hospitalization rate for postsurgical hypoparathyroidism was 1.4/100,000 inhabi- tants per year and the trend showed a significant reduction during the years ( p \ 0.0001). The mean prevalence of hypoparathyroidism among inpatients was 5.3/100,000 inhabitants per year, and there was a significant decrease over the years ( p \ 0.0001). Hypoparathyroidism, partic- ularly the postsurgical form of the disease, is not an uncommon condition among hospitalized patients in Italy. We observed a tendency to a decrease in the frequency of hospitalization during the period 2006–201

Imaging technologies in the differential diagnosis and follow-up of brown tumor in primary hyperparathyroidism: case report and review of the literature

Brown tumors are osteolytic lesions associated with hyperparathyroidism (HPT). They may involve various skeletal segments, but rarely the cranio-facial bones. We report a case of a young boy with a swelling of the jaw secondary to a brown tumor presenting as the first manifestation of primary HPT (PHPT). He was found to have brown tumor located in the skull, as well. Different imaging technologies were employed for the diagnosis and follow-up after parathyroidectomy. We enclose a review of the literature on the employment of such imaging technologies in the differential diagnosis of osteolytic lesions. A multidisciplinary approach comprising clinical, laboratory and imaging findings is essential for the differential diagnosis of brown tumor in PHPT

Solving Quantum Ground-State Problems with Nuclear Magnetic Resonance

Quantum ground-state problems are computationally hard problems; for general many-body Hamiltonians, there is no classical or quantum algorithm known to be able to solve them efficiently. Nevertheless, if a trial wavefunction approximating the ground state is available, as often happens for many problems in physics and chemistry, a quantum computer could employ this trial wavefunction to project the ground state by means of the phase estimation algorithm (PEA). We performed an experimental realization of this idea by implementing a variational-wavefunction approach to solve the ground-state problem of the Heisenberg spin model with an NMR quantum simulator. Our iterative phase estimation procedure yields a high accuracy for the eigenenergies (to the 10^-5 decimal digit). The ground-state fidelity was distilled to be more than 80%, and the singlet-to-triplet switching near the critical field is reliably captured. This result shows that quantum simulators can better leverage classical trial wavefunctions than classical computers.Comment: 11 pages, 13 figure