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Abstract Introduction Growth differentiation factor 15 (GDF15) is a cytokine of the TGFβ family. Here, we analyzed GDF15 levels in patients with locally advanced non-small cell lung cancer (LA-NSCLC) who participated in OCOG-ALMERA (NCT02115464), a phase II randomized clinical trial, that investigated metformin in combination with standard of care concurrent chemoradiotherapy (cCRT). OCOG-ALMERA was not able to demonstrate benefit in the metformin arm. Therefore, biomarker studies are needed to better define stratification parameters for future trials. Methods Patients were randomized to treatment with platinum-based chemotherapy and concurrent chest radiotherapy (60–66 Gy), with or without metformin (2000 mg/d). The trial collected tumor volume parameters, survival outcomes, and patient blood plasma at baseline, during (weeks 1 and 6) and 6 months after cCRT. Plasma GDF15 levels were assayed with the ELISA method. Statistical analyses explored associations between GDF15, survival outcomes, and radiotherapy tumor volumes. Results Baseline plasma levels of GDF15 were elevated in study patients, they increased during cCRT (p

In The Cartographer, the playwright Juan Mayorga recovers for the present, and in an original and oblique way, some of the events that took place in the Warsaw ghetto in the first half of the 1940s. The piece makes explicit a parallelism between cartographic art and theatrical writing and at the same time translates it into practice through its own architecture. The map and the human body become there means of resistance to the impositions of History and vehicles of a memory that strives to save a part of the past and which allows to look at it with a renewed gaze and as an invisible part of the present.

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Congenital cytomegalovirus (cCMV) infection can follow primary and secondary maternal infection. Growing evidence indicate that secondary maternal infections contribute to a much greater proportion of symptomatic cCMV than was previously thought. We performed a monocentric retrospective study of babies with cCMV evaluated from August 2004 to February 2021; we compared data of symptomatic children born to mothers with primary or secondary infection, both at birth and during follow up. Among the 145 babies with available data about maternal infection, 53 were classified as having symptomatic cCMV and were included in the study: 40 babies were born to mothers with primary infection and 13 babies were born to mothers with secondary infection. Analyzing data at birth, we found no statistical differences in the rate of clinical findings in the two groups, except for unilateral sensorineural hearing loss (SNHL) which was significantly more frequent in patients born to mother with secondary infection than in those born to mother with primary infection (46.2 vs. 17.5%, P = 0.037). During follow up, we found a higher rate of many sequelae (tetraparesis, epilepsy, motor and speech delay, and unilateral SNHL) in the group of children born to mothers with secondary infection, with a statistical difference for tetraparesis and unilateral SNHL. Otherwise, only children born to mothers with primary infection presented bilateral SNHL both at birth and follow up. Our data suggest that the risk of symptomatic cCMV and long-term sequelae is similar in children born to mother with primary and secondary CMV infection; it is important to pay appropriate attention to seropositive mothers in order to prevent reinfection and to detect and possibly treat infected babies.

Background/Purpose: Type 2 diabetes and obesity increase the risk of developing colorectal cancer. Metformin may reduce colorectal cancer but the mechanisms mediating this effect remain unclear. In mice and humans, a high-fat diet (HFD), obesity and metformin are known to alter the gut microbiome but whether this is important for influencing tumor growth is not known. Methods: Mice with syngeneic MC38 colon adenocarcinomas were treated with metformin or feces obtained from control or metformin treated mice. Results: We find that compared to chow-fed controls, tumor growth is increased when mice are fed a HFD and that this acceleration of tumor growth can be partially recapitulated through transfer of the fecal microbiome or in vitro treatment of cells with fecal filtrates from HFD-fed animals. Treatment of HFD-fed mice with orally ingested, but not intraperitoneally injected, metformin suppresses tumor growth and increases the expression of short-chain fatty acid (SCFA)-producing microbes Alistipes, Lachnospiraceae and Ruminococcaceae. The transfer of the gut microbiome from mice treated orally with metformin to drug naïve, conventionalized HFD-fed mice increases circulating propionate and butyrate, reduces tumor proliferation, and suppresses the expression of sterol response element binding protein (SREBP) gene targets in the tumor. Conclusion: These data indicate that in obese mice fed a HFD, metformin reduces tumor burden through changes in the gut microbiome.

How do Italians perceive immigrants? Over the last twenty years, the issue of immigration has become increasingly relevant. With the intensification of landings, the issue connected to immigration has become an element of conflict and confrontation both in civil society and in politics. Among the various determinants that explain the attitude towards immigration, religion appears to play a very important role in orienting public opinion. Using some information collected by the European Values ​​survey in the last five years (2016-2018) it emerges that after the 2015 migration peak, Catholics tend to be less positive about immigrants and perceive them as a problem for their culture in general. Over time, the action of the Catholic Church and the effects it has produced on those who participate in religious life have attenuated this negative attitude.

BackgroundDespite a successful antiretroviral therapy (ART), adolescents living with perinatally acquired HIV (PHIV) experience signs of B-cell hyperactivation with expansion of ‘namely’ atypical B-cell phenotypes, including double negative (CD27-IgD-) and termed age associated (ABCs) B-cells (T-bet+CD11c+), which may result in reduced cell functionality, including loss of vaccine-induced immunological memory and higher risk of developing B-cells associated tumors. In this context, perinatally HIV infected children (PHIV) deserve particular attention, given their life-long exposure to chronic immune activation.MethodsWe studied 40 PHIV who started treatment by the 2nd year of life and maintained virological suppression for 13.5 years, with 5/40 patients experiencing transient elevation of the HIV-1 load in the plasma (Spike). We applied a multi-disciplinary approach including immunological B and T cell phenotype, plasma proteomics analysis, and serum level of anti-measles antibodies as functional correlates of vaccine-induced immunity.ResultsPhenotypic signs of B cell hyperactivation were elevated in subjects starting ART later (%DN T-bet+CD11c+ p=0.03; %AM T-bet+CD11c+ p=0.02) and were associated with detectable cell-associated HIV-1 RNA (%AM T-bet+CD11c+ p=0.0003) and transient elevation of the plasma viral load (spike). Furthermore, B-cell hyperactivation appeared to be present in individuals with higher frequency of exhausted T-cells, in particular: %CD4 TIGIT+ were associated with %DN (p=0.008), %DN T-bet+CD11c+ (p=0.0002) and %AM T-bet+CD11c+ (p=0.002) and %CD4 PD-1 were associated with %DN (p=0.048), %DN T-bet+CD11c+ (p=0.039) and %AM T-bet+CD11c+ (p=0.006). The proteomic analysis revealed that subjects with expansion of these atypical B-cells and exhausted T-cells had enrichment of proteins involved in immune inflammation and complement activation pathways. Furthermore, we observed that higher levels of ABCs were associated a reduced capacity to maintain vaccine-induced antibody immunity against measles (%B-cells CD19+CD10- T-bet+, p=0.035).ConclusionWe identified that the levels of hyperactivated B cell subsets were strongly affected by time of ART start and associated with clinical, viral, cellular and plasma soluble markers. Furthermore, the expansion of ABCs also had a direct impact on the capacity to develop antibodies response following routine vaccination.

Reseña de Fausta Antonucci, Calderón de la Barca, Salerno Editrice, Roma, 2020, 364 pp. ISBN: 9788869734960.

Introduction Psychological problems are common among the pediatric population suffering from a chronic illness, especially compared to the normal population. Stressful life events, such as social distancing measures implemented to counter the COVID-19 pandemic emergency, can strongly influence their epidemiology. Objectives The aim of this study was to assess the prevalence rate of depressive and anxiety symptoms among an Italian pediatric population affected by chronic illness and already under a Children Hospital psychological follow-up program during COVID-19 lockdown. Methods We conducted a cross-sectional study among 54 Italian children and adolescents affected by chronic illness (mean age: 15y; range: 8.9-18y) during the COVID-19 epidemic period. We assessed depressive and anxiety symptoms with the Patient Health Questionnaire (PHQ-9) and the Generalized Anxiety Disorders (GAD-7) questionnaire during scheduled follow-up checks or teleconsulting. Results Preliminary results showed an elevated prevalence of depressive and anxiety symptoms (51% and 48% respectively) among chronically ill children during the COVID-19 outbreak. When compared with a non-ill pediatric population (Zhou et al. 2020), rates are + 7.3% higher for depression and + 10.6% for anxiety. Conclusions Chronic ill pediatric patients are a vulnerable group and require careful consideration. For this reason, the healthcare system should be able to implement and guarantee adequate mental health support programs and continuity of care. Further research is necessary since the COVID-19 outbreak could be repeated.

Summary: The antidiabetic drug phenformin displays potent anticancer activity in different tumors, but its mechanism of action remains elusive. Using Shh medulloblastoma as model, we show here that at clinically relevant concentrations, phenformin elicits a significant therapeutic effect through a redox-dependent but complex I-independent mechanism. Phenformin inhibits mitochondrial glycerophosphate dehydrogenase (mGPD), a component of the glycerophosphate shuttle, and causes elevations of intracellular NADH content. Inhibition of mGPD mimics phenformin action and promotes an association between corepressor CtBP2 and Gli1, thereby inhibiting Hh transcriptional output and tumor growth. Because ablation of CtBP2 abrogates the therapeutic effect of phenformin in mice, these data illustrate a biguanide-mediated redox/corepressor interplay, which may represent a relevant target for tumor therapy. : Di Magno et al. investigate the therapeutic properties of phenformin in Hedgehog-dependent tumors. At clinically relevant doses, phenformin works independent of respiratory complex I through mGPD-mediated increase of the redox state. This promotes CtBP2/Gli1 complex formation and consequent inhibition of Hedgehog transcriptional output and tumor growth. Keywords: phenformin, cancer, Hedgehog, complex I, mGPD, NADH, CtBP2, metformin, redox, biguanides

Reseña de Antonio Sánchez Jiménez, Lope de Vega: el verso y la vida, Cátedra (Biografías), Madrid, 2018, 468 pp. ISBN: 9788437638621.

El andamiaje argumental de Mirad a quién alabáis, comedia palatina de la madurez de Lope (princeps: 1621), se sustenta en los retratos verbales que diferentes personajes hacen de la extraordinaria hermosura de Juana Esforcia, Duquesa de Milán. La utilización constante a lo largo de la pieza de referencias pictóricas permite ver estos retratos, de remota ascendencia petrarquista, como una manifestación ecfrástica, a la dama retratada como una viva obra de arte y, sobre todo, al dramaturgo como un insuperable «pintor». Así, la capacidad que poseen las descripciones de suscitar pasiones en escena se convierte en última instancia en un testimonio más, si no en un alarde, de la maestría formal de Lope en años convulsos para su reinado literario y dramático, al mismo tiempo que una mise en abyme de su arte teatral.

The objective of this study is to analyze magnetic resonance imaging shrinkage pattern of tumor regression after neoadjuvant chemotherapy and to evaluate its relationship with biological subtypes and pathological response. We reviewed the magnetic resonance imaging studies of 51 patients with single mass-enhancing lesions (performed at time 0 and at the II and last cycles of neoadjuvant chemotherapy). Tumors were classified as Luminal A, Luminal B, HER2+, and Triple Negative based on biological and immunohistochemical analysis after core needle biopsy. We classified shrinkage pattern, based on tumor regression morphology on magnetic resonance imaging at the II cycle, as concentric, nodular, and mixed. We assigned a numeric score (0: none; 1: low; 2: medium; 3: high) to the enhancement intensity decrease. Pathological response on the surgical specimen was classified as complete (grade 5), partial (grades 4–3), and non-response (grades 1–2) according to Miller and Payne system. Fisher test was used to relate shrinkage pattern with biological subtypes and final pathological response. Seventeen patients achieved complete response, 25 partial response, and 9 non-response. A total of 13 lesions showed nodular pattern, 20 concentric, and 18 mixed. We found an association between concentric pattern and HER2+ (p

Reseña de Felipe B. Pedraza Jiménez, Rafael González Cañal y Elena E. Marcello, eds., El último Lope (1618-1635) y la escena. XXXVI Jornadas de teatro clásico. Almagro, 11, 12 y 13 de julio de 2013, Ediciones de la Universidad de Castilla-La Mancha, [Cuenca], 2015, 288 pp. ISBN: 9788490441404.