PARP inhibitors in endometrial cancer: current status and perspectives

Advanced, recurrent and metastatic endometrial cancer (EC) has a dismal prognosis due to poor response rates to conventional treatments. In the era of precision medicine, the improved understanding of cancer genetics and molecular biology has led to the development of targeted therapies, such as poly (ADP-ribose) polymerase (PARP) inhibitors. This class of drugs that inhibit PARP enzymes has been investigated in many different types of tumors and its use in the treatment of gynecological malignancies has rapidly increased over the past few years. Data from several clinical trials showed that PARP inhibitors have a beneficial role in cancers with a defect in the homologous DNA recombination system, regardless of the BRCA mutational status. Since EC frequently shows mutations in PTEN and TP53 genes, indirectly involved in the homologous DNA recombination pathway, several in vivo and in vitro studies investigated the efficacy of PARP inhibitors in EC, showing promising results. This review will discuss the use of PARP inhibitors in endome-trial cancer, summarizing data from preclinical studies and providing an overview of the ongoing trials, with a special focus on the development of combined treatment strategies with PARP inhibitors and immune checkpoint inhibitors

Contextual influences on italian university students during the covid-19 lockdown: Emotional responses, coping strategies and resilience

none17Based on an ecological perspective on the COVID-19 lockdown experience, this study describes psychological responses among Italian university students. Our study considers three zones of the country that have differed in the intensity of the COVID-19 pandemic. Specifically, this research explores whether differences in pandemic conditions can account for their divergent psychological outcomes. The participants were 792 university students from seven different Italian universities. Students were asked to express their emotions and describe meaningful events during the lockdown in writing. Based on the grounded theory approach, this study conducted qualitative data analysis using ATLAS.ti 8.0. The core emerged categories are emotions, emotional moods and state of mind, coping strategies, and resilience. The results describing these emergent factors in relation to environmental variables highlight differences in the feeling of anxiety among individuals: anxiety was more self-focused in zones that were more affected by the lockdown, while such anxiety was more related to family and friends in less-affected zones. In addition to identifying the negative repercussions that this emergency has had, this study describes some positive outcomes, such as the elaboration of new personal perspectives that help foster individual growth and allow individuals to gain new awareness of themselves and others. The confinement due to the COVID-19 emergency measures has been a very unique experience for people, and further research is needed to understand the long-term effects of the different coping responses activated by participants during and after the lockdown.mixedLaura Migliorini; Norma De Piccoli; Paola Cardinali; Chiara Rollero; Daniela Marzana; Caterina Arcidiacono; Elisa Guidi; Ciro Esposito; Cinzia Novara; Angela Fedi; Elena Marta; Andrea Guazzini; Patrizia Meringolo; Maria Grazia Monaci; Barbara Agueli; Fortuna Procentese; Immacolata Di NapoliMigliorini, Laura; De Piccoli, Norma; Cardinali, Paola; Rollero, Chiara; Marzana, Daniela; Arcidiacono, Caterina; Guidi, Elisa; Esposito, Ciro; Novara, Cinzia; Fedi, Angela; Marta, Elena; Guazzini, Andrea; Meringolo, Patrizia; Grazia Monaci, Maria; Agueli, Barbara; Procentese, Fortuna; Di Napoli, Immacolat

Dendritic cell viability is decreased after phagocytosis of apoptotic tumor cells induced by staurosporine or vaccinia virus infection

Background and Objectives. Dendritic cells (DC) primed with tumor antigens can effectively mediate the regression of a variety of established solid malignancies in both murine and human models. Several experimental studies indicate that apoptotic bodies are an optimal source of tumor antigens for ex vivo priming of DC. However, the clinical use of killed tumor cells as a source of antigens will require an optimal methodology to induce effective tumor cell apoptosis. Design and Methods. The goal of this study was to compare the efficiency of three agents for inducing neoplastic B lymphocyte apoptosis; staurosporine, infection by modified vaccinia (MVA) viral particles and ultraviolet C (UVC) radiation. Results. The three methods were finely tuned to induce apoptosis in more than 90% of tumor cells after 24 hours of exposure. However, the viability of monocyte-derived DC, loaded with B-cell tumor apoptotic bodies induced by staurosporine or MVA viral particles, decreased dramatically within 48 hours after phagocytosis of the killed neoplastic cells. The persistence of the apoptosis-inducing agents in the apoptotic bodies and not in the tumor supernatant, was responsible for the observed damage to DC viability. In contrast, DC viability was not affected after uptake of tumor cells killed through UVC-irradiation. Furthermore, B-lymphoblastic cell line (LCL)-specific T cells were reactivated by DC loaded with apoptotic bodies induced by UVC-rays. Interpretation and Conclusions. Since the method used to induce tumor cell apoptosis might be detrimental to DC viability, these findings should be considered when designing anticancer vaccination programs

Study of the time and space distribution of beta+ emitters from 80 MeV/u carbon ion beam irradiation on PMMA

Proton and carbon ion therapy is an emerging technique used for the treatment of solid cancers. The monitoring of the dose delivered during such treatments and the on-line knowledge of the Bragg peak position is still a matter of research. A possible technique exploits the collinear 511\ \kilo\electronvolt photons produced by positrons annihilation from $\beta^+$ emitters created by the beam. This paper reports rate measurements of the 511\ \kilo\electronvolt photons emitted after the interactions of a 80\ \mega\electronvolt / u fully stripped carbon ion beam at the Laboratori Nazionali del Sud (LNS) of INFN, with a Poly-methyl methacrylate target. The time evolution of the $\beta^+$ rate was parametrized and the dominance of $^{11}C$ emitters over the other species ($^{13}N$, $^{15}O$, $^{14}O$) was observed, measuring the fraction of carbon ions activating $\beta^+$ emitters $A_0=(10.3\pm0.7)\cdot10^{-3}$. The average depth in the PMMA of the positron annihilation from $\beta^+$ emitters was also measured, D_{\beta^+}=5.3\pm1.1\ \milli\meter, to be compared to the expected Bragg peak depth D_{Bragg}=11.0\pm 0.5\ \milli\meter obtained from simulations

Observation of the TeV gamma-ray source MGRO J1908+06 with ARGO-YBJ

The extended gamma ray source MGRO J1908+06, discovered by the Milagro air shower detector in 2007, has been observed for about 4 years by the ARGO-YBJ experiment at TeV energies, with a statistical significance of 6.2 standard deviations. The peak of the signal is found at a position consistent with the pulsar PSR J1907+0602. Parametrizing the source shape with a two-dimensional Gauss function we estimate an extension \sigma = 0.49 \pm 0.22 degrees, consistent with a previous measurement by the Cherenkov Array H.E.S.S.. The observed energy spectrum is dN/dE = 6.1 \pm 1.4 \times 10^-13 (E/4 TeV)^{-2.54 \pm 0.36} photons cm^-2 s^-1 TeV^-1, in the energy range 1-20 TeV. The measured gamma ray flux is consistent with the results of the Milagro detector, but is 2-3 times larger than the flux previously derived by H.E.S.S. at energies of a few TeV. The continuity of the Milagro and ARGO-YBJ observations and the stable excess rate observed by ARGO-YBJ along 4 years of data taking support the identification of MGRO J1908+06 as the steady powerful TeV pulsar wind nebula of PSR J1907+0602, with an integrated luminosity above 1 TeV about 1.8 times the Crab Nebula luminosity.Comment: 6 pages, accepted for pubblication by ApJ. Replaced to correct the author lis

Gene signature and immune cell profiling by high-dimensional, single-cell analysis in COVID-19 patients, presenting Low T3 syndrome and coexistent hematological malignancies

BACKGROUND: Low T3 syndrome is frequent in patients admitted to intensive care units for critical illness and pneumonia. It has been reported also in patients with COVID-19, Hodgkin disease and chronic lymphocytic leukemia. We analyzed the clinical relevance of Low T3 syndrome in COVID-19 patients and, in particular, in those with associated hematological malignancies.METHODS: Sixty-two consecutive patients, hospitalized during the first wave of SARS-CoV-2 outbreak in Sant'Andrea University Hospital in Rome, were subdivided in 38 patients (Group A), showing low levels of FT3, and in 24 patients (Group B), with normal FT3 serum values. During the acute phase of the disease, we measured serum, radiologic and clinical disease severity markers and scores, in search of possible correlations with FT3 serum values. In addition, in 6 COVID-19 patients, 4 with Low T3 syndrome, including 2 with a hematological malignancy, and 2 with normal FT3 values, we performed, high-dimensional single-cell analysis by mass cytometry, multiplex cytokine assay and gene expression profiling in peripheral blood mononuclear cells (PBMC).RESULTS: Low FT3 serum values were correlated with increased Absolute Neutrophil Count, NLR and dNLR ratios and with reduced total count of CD3+, CD4+ and CD8+ T cells. Low FT3 values correlated also with increased levels of inflammation, tissue damage and coagulation serum markers as well as with SOFA, LIPI and TSS scores. The CyTOF analysis demonstrated reduction of the effector memory and terminal effector subtypes of the CD4+ T lymphocytes. Multiplex cytokine assay indicates that mainly IL-6, IP-10 and MCAF changes are associated with FT3 serum levels, particularly in patients with coexistent hematological malignancies. Gene expression analysis using Nanostring identified four genes differently expressed involved in host immune response, namely CD38, CD79B, IFIT3 and NLRP3.CONCLUSIONS: Our study demonstrates that low FT3 serum levels are associated with severe COVID-19. Our multi-omics approach suggests that T3 is involved in the immune response in COVID-19 and coexistent hematological malignancy and new possible T3 target genes in these patients have been identified

Assessing undergraduates’ perception of risks related to body art in italy: The superba multicenter cross-sectional study

Tattooing and piercing may lead to health complications. The present multicenter cross-sectional study aimed to assess awareness and knowledge of health risks related to body art and to identify their possible determinants among a large sample of undergraduates in Italy. A web-based questionnaire collecting information on socio-demographic characteristics, awareness, knowledge, and some potential predictors was administered to undergraduates attending twelve Italian univer-sities. The level of knowledge was expressed as the number of correct answers (0–11 for tattooing, 0–14 for piercing). A total of 2985 participants (mean age 23.15 ± 3.99, 73.9% F) participated in the study. Although 95.4% of the respondents were aware of possible health consequences of body art, a low level of specific knowledge was registered for both tattooing (mean number of correct answers 5.38 ± 2.39) and piercing (5.93 ± 3.12) consequences. Lower knowledge was associated with the attendance of non-life science course and with lower duration of academic education for both tattoo and piercing. Lower knowledge of tattooing risks was related with commuter status, while lower knowledge of piercing risks was associated with lower father’s education. These findings highlight the need to enhance information campaigns targeted to youths to increase their awareness of possible health risk of body art

C-reactive protein in the very early phase of acute ischemic stroke: association with poor outcome and death

Acute ischemic stroke may trigger an inflammatory response that leads to increased levels of C-reactive protein (CRP). High levels of CRP may be associated with poor outcome because they reflect either an inflammatory reaction or tissue damage. We evaluated the prognostic value of CRP within 12 h of onset of ischemic stroke. Levels of CRP were routinely obtained within 12 h of symptom onset in 561 patients with ischemic stroke. CRP values were dichotomized as <7 or ≥7 mg/L. The full range of CRP values was used to detect a possible level-risk relationship. We studied the relation between CRP values and poor outcome (modified Rankin Scale score >2) or death at 3 months. A multiple logistic regression model was applied to adjust for age, sex, NIHSS score, current cigarette smoking, diabetes mellitus, hypertension, statin use, and stroke subtype. After adjustment for potential confounders, patients with CRP levels ≥7 mg/L had a significantly increased risk of poor outcome (adjusted OR 1.6, 95% CI 1.1–2.4) or death (adjusted OR 1.7, 95% CI 1.0–2.9) at 3 months. In addition, the risk of poor outcome or death at 3 months increased with higher levels of CRP. CRP within 12 h of ischemic stroke is an independent prognostic factor of poor outcome at 3 months

The risk stratification of adverse neonatal outcomes in women with gestational diabetes (STRONG) study

Aims: To assess the risk of adverse neonatal outcomes in women with gestational diabetes (GDM) by identifying subgroups of women at higher risk to recognize the characteristics most associated with an excess of risk. Methods: Observational, retrospective, multicenter study involving consecutive women with GDM. To identify distinct and homogeneous subgroups of women at a higher risk, the RECursive Partitioning and AMalgamation (RECPAM) method was used. Overall, 2736 pregnancies complicated by GDM were analyzed. The main outcome measure was the occurrence of adverse neonatal outcomes in pregnancies complicated by GDM. Results: Among study participants (median age 36.8 years, pre-gestational BMI 24.8 kg/m2), six miscarriages, one neonatal death, but no maternal death was recorded. The occurrence of the cumulative adverse outcome (OR 2.48, 95% CI 1.59–3.87), large for gestational age (OR 3.99, 95% CI 2.40–6.63), fetal malformation (OR 2.66, 95% CI 1.00–7.18), and respiratory distress (OR 4.33, 95% CI 1.33–14.12) was associated with previous macrosomia. Large for gestational age was also associated with obesity (OR 1.46, 95% CI 1.00–2.15). Small for gestational age was associated with first trimester glucose levels (OR 1.96, 95% CI 1.04–3.69). Neonatal hypoglycemia was associated with overweight (OR 1.52, 95% CI 1.02–2.27) and obesity (OR 1.62, 95% CI 1.04–2.51). The RECPAM analysis identified high-risk subgroups mainly characterized by high pre-pregnancy BMI (OR 1.68, 95% CI 1.21–2.33 for obese; OR 1.38 95% CI 1.03–1.87 for overweight). Conclusions: A deep investigation on the factors associated with adverse neonatal outcomes requires a risk stratification. In particular, great attention must be paid to the prevention and treatment of obesity