Predictive and prognostic value of inflammatory markers in locally advanced rectal cancer (PILLAR) – A multicentric analysis by the Italian Association of Radiotherapy and Clinical Oncology (AIRO) Gastrointestinal Study Group

Background: Patients (pts) affected with locally advanced rectal cancer (LARC) may respond differently to neoadjuvant chemoradiotherapy (nCRT). The identification of reliable biomarkers able to predict oncological outcomes could help in the development of risk-adapted treatment strategies. It has been suggested that inflammation parameters may have a role in predicting tumor response to nCRT and survival outcomes and in rectal cancer, but no definitive conclusion can be drawn at present. The aim of the current study is to evaluate the role of baseline inflammatory markers as prognostic and predictive factors in a large multicentric Italian cohort of LARC pts. Methods: Patients diagnosed with LARC from January 2002 to December 2019 in 9 Italian centers were retrospectively collected. Patients underwent long-course RT with chemotherapy based on fluoropyrimidine ± oxaliplatin followed by surgery. Inflammatory markers were retrieved based on a pre-treatment blood sample including HEI (hemo-eosinophils inflammation index), SII (systemic index of inflammation), NLR (neutrophil-to-lymphocyte ratio), PLR (platelet-to-lymphocyte ratio) and MLR (monocyte-to-lymphocyte ratio). Outcomes of interest were pathological complete response (pCR), disease-free survival (DFS), and overall survival (OS). Results: 808 pts were analyzed. pCR rate was 22 %, 5yOS and 5yDFS were 84.0% and 63.1% respectively. Multivariate analysis identified that a NLR cut-off value >1.2 and SII cut-off value >500 could predict pCR (p = 0.05 and 0.009 respectively). In addition to age, extramesorectal nodes and RT dose, MLR >0.18 (p = 0.03) and HEI = 3 (p = 0.05) were independent prognostic factors for DFS. Finally, age, RT dose, MLR with a cut-off >0.35 (p = 0.028) and HEI = 3 (p = 0.045) were independent predictors of OS. Conclusions: Higher values of baseline composite inflammatory markers can serve as predictors of lower pCR rates and worse survival outcomes in LARC patients undergoing nCRT. More reliable data from prospective studies could lead to the integration of these inexpensive and easy-to-derive tools into clinical practice

Tribbles-1 expression and its function to control inflammatory cytokines, including interleukin-8 levels are regulated by miRNAs in macrophages and prostate cancer cells

The pseudokinase TRIB1 controls cell function in a range of contexts, by regulating MAP kinase activation and mediating protein degradation via the COP1 ubiquitin ligase. TRIB1 regulates polarization of macrophages and dysregulated Trib1 expression in murine models has been shown to alter atherosclerosis burden and adipose homeostasis. Recently, TRIB1 has also been implicated in the pathogenesis of prostate cancer, where it is often overexpressed, even in the absence of genetic amplification. Well described TRIB1 effectors include MAP kinases and C/EBP transcription factors, both in immune cells and in carcinogenesis. However, the mechanisms that regulate TRIB1 itself remain elusive. Here, we show that the long and conserved 3’untranslated region (3’UTR) of TRIB1 is targeted by miRNAs in macrophage and prostate cancer models. By using a systematic in silico analysis, we identified multiple “high confidence” miRNAs potentially binding to the 3’UTR of TRIB1 and report that miR-101-3p and miR-132-3p are direct regulators of TRIB1 expression and function. Binding of miR-101-3p and miR-132-3p to the 3’UTR of TRIB1 mRNA leads to an increased transcription and secretion of interleukin-8. Our data demonstrate that modulation of TRIB1 by miRNAs alters the inflammatory profile of both human macrophages and prostate cancer cells

Extending the tephra and palaeoenvironmental record of the Central Mediterranean back to 430 ka: A new core from Fucino Basin, central Italy

Here we present the first tephrostratigraphic, palaeomagnetic, and multiproxy data from a new ∼98 m-deep sediment core retrieved from the Fucino Basin, central Italy, spanning the last ∼430 kyr. Palaeoenvironmental proxy data (Ca-XRF, gamma ray and magnetic susceptibility) show a cyclical variability related to interglacial-glacial cycles since the Marine Isotope Stage (MIS) 12-MIS 11 transition. More than 130 tephra layers are visible to the naked eye, 11 of which were analysed (glass-WDS) and successfully correlated to known eruptions and/or other equivalent tephra. In addition to tephra already recognised in the previously investigated cores spanning the last 190 kyr, we identified for the first time tephra from the eruptions of: Tufo Giallo di Sacrofano, Sabatini (288.0 ± 2.0 ka); Villa Senni, Colli Albani (367.5 ± 1.6 ka); Pozzolane Nere and its precursor, Colli Albani (405.0 ± 2.0 ka, and 407.1 ± 4.2 ka, respectively) and Castel Broco, Vulsini (419–490 ka). The latter occurs at the bottom of the core and has been 40Ar/39Ar dated at 424.3 ± 3.2 ka, thus providing a robust chronological constrain for both the eruption itself and the base of the investigated succession. Direct 40Ar/39Ar dating and tephra geochemical fingerprinting provide a preliminary radioisotopic-based chronological framework for the MIS 11-MIS 7 interval, which represent a foundation for the forthcoming multiproxy studies and for investigating the remaining ∼110 tephra layers that are recorded within this interval. Such future developments will contribute towards an improved MIS 11-MIS 7 Mediterranean tephrostratigraphy, which is still poorly explored and exploited

Pleistocene tephrostratigraphy and palaeoclimatology in the central Mediterranean region: ongoing research in Fucino Basin (central Apennines, Italy)

Palaeoclimatic records spanning beyond the radiocarbon range generally derive their chronologies from orbital tuning strategies. These chronologies can introduce a priori assumptions that are difficult to test and, possibly, circular arguments in palaeoclimatic reconstructions. We elaborate two high-resolution, multi-proxy and tephrochronologically-constrained records (F1-F3 and F4-F5) of past environmental and climatic changes in the central Mediterranean region. We perform geochemical (X-ray fluorescence scanning, carbon, nitrogen and sulphur elemental analysis through combustion), isotopic (C and O stable isotope mass spectrometry on bulk carbonates and organic matter), mineralogical (X-ray powder diffraction) and grain-size analyses on lacustrine marls recovered from palaeolake Fucino (Abruzzo, central Italy). Lacustrine sediments were acquired during two scientific drilling campaigns (F1-F3 and F4-F5) interesting the first ca. 85 m of the 1 km-thick and 2 Ma-old Fucino sedimentary succession. We make use of detailed tephrostratigraphic and tephrochronological frameworks to produce robust and independent chronologies based on new and published 40Ar/39Ar and 14C dating of tephra layers. On the basis of our chronologies, the F1-F3 and F4-F5 records continuously span over the last two glacial-interglacial cycles and over the last five glacial-interglacial cycles, respectively. We combine our geological data into proxies for catchment- and regional-scale environmental processes. Our proxy time-series depict prominent orbital and sub-orbital environmental changes that can be tracked in other lacustrine, marine and speleothem records across the Mediterranean and North Atlantic regions. Thanks to tephrostratigraphic correlations and chronological matching, we produce spatially coherent palaeoclimatic reconstructions recognising a complex interplay between regional environmental processes and broad-scale climatic events. We highlight strong orbital forcing for past climate changes

Neutrophil microvesicles drive atherosclerosis by delivering <i>miR-155</i> to atheroprone endothelium

Neutrophils are implicated in the pathogenesis of atherosclerosis but are seldom detected in atherosclerotic plaques. We investigated whether neutrophil-derived microvesicles may influence arterial pathophysiology. Here we report that levels of circulating neutrophil microvesicles are enhanced by exposure to a high fat diet, a known risk factor for atherosclerosis. Neutrophil microvesicles accumulate at disease-prone regions of arteries exposed to disturbed flow patterns, and promote vascular inflammation and atherosclerosis in a murine model. Using cultured endothelial cells exposed to disturbed flow, we demonstrate that neutrophil microvesicles promote inflammatory gene expression by delivering miR-155, enhancing NF-κB activation. Similarly, neutrophil microvesicles increase miR-155 and enhance NF-κB at disease-prone sites of disturbed flow in vivo. Enhancement of atherosclerotic plaque formation and increase in macrophage content by neutrophil microvesicles is dependent on miR-155. We conclude that neutrophils contribute to vascular inflammation and atherogenesis through delivery of microvesicles carrying miR-155 to disease-prone regions

Genomic and functional regulation of TRIB1 contributes to prostate cancer pathogenesis

Prostate cancer is the most frequent malignancy in European men and the second worldwide. One of the major oncogenic events in this disease includes amplification of the transcription factor cMYC. Amplification of this oncogene in chromosome 8q24 occurs concomitantly with the copy number increase in a subset of neighboring genes and regulatory elements, but their contribution to disease pathogenesis is poorly understood. Here we show that TRIB1 is among the most robustly upregulated coding genes within the 8q24 amplicon in prostate cancer. Moreover, we demonstrate that TRIB1 amplification and overexpression are frequent in this tumor type. Importantly, we find that, parallel to its amplification, TRIB1 transcription is controlled by cMYC. Mouse modeling and functional analysis revealed that aberrant TRIB1 expression is causal to prostate cancer pathogenesis. In sum, we provide unprecedented evidence for the regulation and function of TRIB1 in prostate cancer

Mediterranean winter rainfall in phase with African monsoons during the past 1.36 million years

Mediterranean climates are characterized by strong seasonal contrasts between dry summers and wet winters. Changes in winter rainfall are critical for regional socioeconomic development, but are difficult to simulate accurately1 and reconstruct on Quaternary timescales. This is partly because regional hydroclimate records that cover multiple glacial–interglacial cycles2,3 with different orbital geometries, global ice volume and atmospheric greenhouse gas concentrations are scarce. Moreover, the underlying mechanisms of change and their persistence remain unexplored. Here we show that, over the past 1.36 million years, wet winters in the northcentral Mediterranean tend to occur with high contrasts in local, seasonal insolation and a vigorous African summer monsoon. Our proxy time series from Lake Ohrid on the Balkan Peninsula, together with a 784,000-year transient climate model hindcast, suggest that increased sea surface temperatures amplify local cyclone development and refuel North Atlantic low-pressure systems that enter the Mediterranean during phases of low continental ice volume and high concentrations of atmospheric greenhouse gases. A comparison with modern reanalysis data shows that current drivers of the amount of rainfall in the Mediterranean share some similarities to those that drive the reconstructed increases in precipitation. Our data cover multiple insolation maxima and are therefore an important benchmark for testing climate model performance

"Un minuto per la vita": Tecniche rianimatorie in lattanti a rischio di morte improvvisa. Realizzazione di un video didattico per i genitori. ["A minute for life": resuscitation techniques in infants with risk for sudden infant death syndrome. Development of an instructional video for parents]

Aim. The present study describes a project carried out in the Center for SIDS/ALTE of the Pediatric Clinic of Varese, targeted to deliver and provide parents with a movies on PBLS titled "A Minute for Life". The impact on the parent was evaluated by applying a questionnaire.Methods. The movie "A Minute for Life" was given to 308 parents (122 fathers, mean age 35.2 and 186 mothers, mean age 28.4). All parents completed a questionnaire based on 4 parameters: 1. clarity of the content presented; 2. anxiety felt while watching the movie clip 3. reassurance related to their ability to review other times the movie; 4. the perception of its usefulness.Results. Regarding the clarity of content, the results provide evidence :that 231 parents (75% of the sample) rated him "very clear", while 77 subjects (25%) considered it "quite clear". On the possibility of being able to have at home, 277 parents (90% of subjects) believed it would be very reassuring to see it back Home. According to 231 parents (75% of the sample) the vision of the movie does not convey anxiety, while 77 of them (25% of subjects) felt slightly concerned in relation to vision. With regard to the overall assessment of the movie, all parents (308, 100% of the sample) agreed about its extreme usefulness.Conclusion. Our study opens the way for further prospective studies regarding the appropriateness and usefulness of the movie. It's also important to consider the release of the movie to all new parents and the possibility of giving first aid courses open to all those who want to be able to act with promptness and expertise if and when necessary.Aim. The present study describes a project carried out in the Center for SIDS/ALTE of the Pediatric Clinic of Varese, targeted to deliver and provide parents with a movies on PBLS titled "A Minute for Life". The impact on the parent was evaluated by applying a questionnaire. Methods. The movie "A Minute for Life" was given to 308 parents (122 fathers, mean age 35.2 and 186 mothers, mean age 28.4). All parents completed a questionnaire based on 4 parameters: 1. clarity of the content presented; 2. anxiety felt while watching the movie clip 3. reassurance related to their ability to review other times the movie; 4. the perception of its usefulness. Results. Regarding the clarity of content, the results provide evidence that 231 parents (75% of the sample) rated him "very clear", while 77 subjects (25%) considered it "quite clear". On the possibility of being able to have at home, 277 parents (90% of subjects) believed it would be very reassuring to see it back Home. According to 231 parents (75% of the sample) the vision of the movie does not convey anxiety, while 77 of them (25% of subjects) felt slightly concerned in relation to vision. With regard to the overall assessment of the movie, all parents (308, 100% of the sample) agreed about its extreme usefulness. Conclusion. Our study opens the way for further prospective studies regarding the appropriateness and usefulness of the movie. It's also important to consider the release of the movie to all new parents and the possibility of giving first aid courses open to all those who want to be able to act with promptness and expertise if and when necessary