CT-based tumour response criteria compared after combined treatment for liver metastases of colorectal cancer

open6noPurpose: The aim of this analysis is to compare different tumour response criteria (TRC) after chemotherapy combined with bevacizumab in liver metastases from colorectal cancer (mCRC) to ascertain the best early prognostic indicator of response. Methods and Materials: 103 target liver metastases from 65 mCRC patients treated with chemoterapy plus bevacizumab were examined at the Istituto Oncologico Veneto IOV-IRCSS (March 2008-January 2013). All patients had baseline CT and at least one follow-up scan. Tumour response was retrospectively analyzed by two radiologists using RECIST1.1, modified Choi, and Chun morphologic criteria. Tumour response, classified as good (complete or partial response) or poor (stable or progressive disease), was compared with progression-free survival (PFS) at first follow-up (t1) and time of best response. Interobserver agreement and concordance between TRC were measured. Results: At t1, 32.31% showed a good response according to RECIST1.1 (median PFS 11.1), 84.62% according to Choi (median PFS 10.8). These percentages rose to 49.23% (median PFS 12.1) and 87.69% (median PFS 10.8), respectively, at the time of best response. According to Chun, 67.69% showed a good response at the time of best response (median PFS 10.8). The Choi criteria detected a higher proportion of good responders at t1, showing a better correlation with PFS; all methods correlated with PFS at the time of best response. Conclusion: The Choi criteria proved more consistent in the early detection of response in mCRC treated with chemotherapy plus bevacizumab, underscoring the importance of using these criteria in the early assessment of response to combined treatment.openopenVarotto, A.; Di Grazia, L.; Aliberti, C.; Bergamo, F.; Nardin, M.; Pomerri, F.Varotto, A.; Di Grazia, L.; Aliberti, C.; Bergamo, F.; Nardin, M.; Pomerri, Fabi

Metformin: a modulator of bevacizumab activity in cancer? A case report.

Recurrent type I endometrial cancer ((EC)) has poor prognosis and demands novel therapeutic approaches. Bevacizumab, a VEGF-A neutralizing monoclonal antibody, has shown clinical activity in this setting. To our knowledge, however, although some diabetic cancer patients treated with bevacizumab may also take metformin, whether metformin modulates response to anti-VEGF therapy has not yet been investigated. Here, we report the case of a patient with advanced (EC) treated, among other drugs, with bevacizumab in combination with metformin. The patient affected by relapsed (EC) G3 type 1, presented in march 2010 with liver, lungs and mediastinic metastases. After six cycles of paclitaxel and cisplatin she underwent partial response. Later on, she had disease progression notwithstanding administration of multiple lines of chemotherapy. In march 2013, due to brain metastases with coma, she began steroid therapy with development of secondary diabetes. At this time, administration of Bevacizumab plus Metformin improved her performance status. CT scans performed in this time window showed reduced radiologic density of the lung and mediastinic lesions and of liver disease, suggestive of increased tumor necrosis. Strong F-18-FDG uptake by PET imaging along with high levels of monocarboxylate transporter 4 and lack of liver kinase B1 expression in liver metastasis, highlighted metabolic features previously associated with response to anti-VEGF therapy and phenformin in preclinical models. However, clinical benefit was transitory and was followed by rapid and fatal disease progression. These findingsalbeit limited to a single casesuggest that tumors lacking LKB1 expression and/or endowed with an highly glycolytic phenotype might develop large necrotic areas following combined treatment with metformin plus bevacizumab. As metformin is widely used among diabetes patients as well as in ongoing clinical trials in cancer patients, these results deserve further clinical investigation

Selection of Candidates for Lung Transplantation: The First Italian Consensus Statement

Lung transplantation is a well-established treatment for selected patients with advanced chronic respiratory insufficiency. Recognizing those patients with end-stage lung disease who might benefit from lung transplantation is a crucial task. Considering the presence of inadequate evidence-based practice, international and national scientific societies provided consensus opinions regarding the appropriate timing of listing. The Study Group for Thoracic Organs Transplantation (branch of the Italian Society for Organs Transplantation) promoted and realized a Delphi conference among the Italian lung transplantation centers to provide guidance to clinical practice based on international recommendations. The experts from the nine Italian centers completed two rounds of standardized questionnaires (answer rate, 100%): 42 statements received a consensus >= 80%. The selected statements presented in this article are intended to assist Italian clinicians in selecting patients for lung transplantation

Phenotypic and Molecular Selection of a Superior Solanum pennellii Introgression Sub-Line Suitable for Improving Quality Traits of Cultivated Tomatoes

The Solanum pennellii Introgression Line (IL) population can be exploited to identify favorable alleles that can improve yield and fruit quality traits in commercial tomato varieties. Over the past few years, we have selected ILs that exhibit increased content of antioxidant compounds in the fruit compared to the cultivar M82, which represents the genetic background in which the different wild regions of the S. pennellii ILs were included. Recently, we have identified seven sub-lines of the IL7-3 accumulating different amounts of antioxidants in the ripe fruit. Since the wild region carried on chromosome 7 induces a low fruit production in IL7-3, the first aim of the present work was to evaluate yield performances of the selected sub-lines in three experimental fields located in the South of Italy. Another aim was to confirm in the same lines the high levels of antioxidants and evaluate other fruit quality traits. On red ripe fruit, the levels of soluble solids content, firmness, and ascorbic acid (AsA) were highly variable among the sub-lines grown in three environmental conditions, evidencing a significant genotype by environment interaction for soluble solids and AsA content. Only one sub-line (coded R182) exhibited a significantly higher firmness, even though no differences were observed for this trait between the parental lines M82 and IL7-3. The same sub-line showed significantly higher AsA content compared to M82, thus resembling IL7-3. Even though IL7-3 always exhibited a significantly lower yield, all the sub-lines showed yield variability over the three trials. Interestingly, the sub-line R182, selected for its better performances in terms of fruit quality, in all the trials showed a production comparable to that of the control line M82. A group of species-specific molecular markers was tested on R182 and on the parental genotypes in order to better define the wild genomic regions carried by the elite line R182. In these regions three candidate genes that could increase the level of AsA in the fruit were identified. In the future, the line R182 could be used as pre-breeding material in order to obtain new varieties improved for nutritional traits

Genomic dissection of a wild region in a superior Solanum pennellii introgression sub‐line with high ascorbic acid accumulation in tomato fruit

The Solanum pennellii introgression lines (ILs) have been exploited to map quantitative trait loci (QTLs) and identify favorable alleles that could improve fruit quality traits in tomato varieties. Over the past few years, ILs exhibiting increased content of ascorbic acid in the fruit have been selected, among which the sub‐line R182. The aims of this work were to identify the genes of the wild donor S. pennellii harbored by the sub‐line and to detect genes controlling ascorbic acid accumulation by using genomics tools. A Genotyping‐By‐Sequencing (GBS) approach confirmed that no wild introgressions were present in the sub‐line besides one region on chromosome 7. By using a dense single nucleotide polymorphism (SNP) map obtained by RNA sequencing (RNA‐ Seq), the wild region of the sub‐line was finely identified; thus, defining 39 wild genes that replaced 33 genes of the ILs genetic background (cv. M82). The differentially expressed genes mapping in the region and the variants detected among the cultivated and the wild alleles evidenced the potential role of the novel genes present in the wild region. Interestingly, one upregulated gene, annotated as a major facilitator superfamily protein, showed a novel structure in R182, with respect to the parental lines. These genes will be further investigated using gene editing strategies

A non-linear autoregressive model for indoor air-temperature predictions in smart buildings

In recent years, the contrast against energy waste and pollution has become mandatory and widely endorsed. Among the many actors at stake, the building sector energy management is one of the most critical. Indeed, buildings are responsible for 40% of total energy consumption only in Europe, affecting more than a third of the total pollution produced. Therefore, energy control policies of buildings (for example, forecast-based policies such as Demand Response and Demand Side Management) play a decisive role in reducing energy waste. On these premises, this paper presents an innovative methodology based on Internet-of-Things (IoT) technology for smart building indoor air-temperature forecasting. In detail, our methodology exploits a specialized Non-linear Autoregressive neural network for short-and medium-term predictions, envisioning two different exploitation: (i) on realistic artificial data and (ii) on real data collected by IoT devices deployed in the building. For this purpose, we designed and optimized four neural models, focusing respectively on three characterizing rooms and on the whole building. Experimental results on both a simulated and a real sensors dataset demonstrate the prediction accuracy and robustness of our proposed models

Prevalence and incidence of bronchiectasis in Italy

BACKGROUND: The understanding of the epidemiology of bronchiectasis is still affected by major limitations with very few data published worldwide. The aim of this study was to estimate the epidemiological burden of bronchiectasis in Italy in the adult population followed-up by primary care physicians. METHODS: This study analyzed data coming from a large primary care database with 1,054,376 subjects in the period of time 2002-2015. Patients with bronchiectasis were selected by the use of International Statistical Classification of Diseases, 9th revision, Clinical Modification codes (ICD-9-CM). RESULTS: Patients with bronchiectasis were more likely to have a history of tuberculosis (0.47% vs. 0.06%, p\u2009<\u20090.0001), had higher rates of asthma (16.6% vs. 6.2%, p\u2009<\u20090.0001), COPD (23.3% vs. 6.4%, p\u2009<\u20090.0001) and rheumatoid arthritis (1.9% vs. 0.8%, p\u2009<\u20090.0001). The prevalence and incidence of bronchiectasis in primary care in Italy in 2015 were 163 per 100,000 population and 16.3 per 100,000 person-years, respectively. Prevalence and incidence increased with age and overall rates were highest in men over 75\u2009years old. Prevalence and incidence computed after the exclusion of patients with a diagnosis of either asthma or COPD is 130 per 100,000 and 11.1 cases per 100,000 person-years, respectively. CONCLUSIONS: Bronchiectasis is not a rare condition in Italian adult population. Further studies are needed to confirm our results and provide a better insight on etiology of bronchiectasis in Italy

Fertilisation with compost mitigates salt stress in tomato by affecting plant metabolomics and nutritional profiles

Background: Salinity is one of the major threats for crop growth and yield and its rate of expansion is expected to increase. We conducted a pot experiment to evaluate and compare the effect of a green compost addition and mineral fertilisation, on growth, nutrition and metabolites of tomato plants, exposed to increasing doses of NaCl. Results: Although the development of stressed plants was lower than the corresponding controls, compost-treated plants performed better than mineral-amended plants watered with the same amount of salt. The different plant growth was related to an increased nutritional status. Namely, compost-treated plants showed a larger content of macro- and micronutrients, and a greater accumulation of osmoprotectants, such as soluble sugars and amino acids. Moreover, compost-treated plants showed a larger content of metabolites involved in modulating the response to salt stress, such as molecules related to energy transfer in plants and precursors of Reactive Oxygen Species scavenging compounds. Overall, the better performance of compost-added plants may be attributed to a greater availability of the organic forms of nutrients and to the positive bioactivity of compost-derived humic substances. Conclusions: Compost application efficiently mitigated salt stress in tomato plants in respect to mineral fertilisation. This alleviating role was associated to the induction of a more efficient metabolic response that increased accumulation of metabolites involved in modulating the salinity stress. Therefore, fertilising with composted agricultural residue may represent a convenient alternative to mineral fertilisers to grow tomato plants in the presence of salt stres

From Ivacaftor to Triple Combination: A Systematic Review of Efficacy and Safety of CFTR Modulators in People with Cystic Fibrosis

Over the last years CFTR (cystic fibrosis transmembrane conductance regulator) modulators have shown the ability to improve relevant clinical outcomes in patients with cystic fibrosis (CF). This review aims at a systematic research of the current evidence on efficacy and tolerability of CFTR modulators for different genetic subsets of patients with CF. Two investigators independently performed the search on PubMed and included phase 2 and 3 clinical trials published in the study period 1 January 2005\u201331 January 2020. A final pool of 23 papers was included in the systematic review for a total of 4219 patients. For each paper data of interest were extracted and reported in table. In terms of lung function, patients who had the most beneficial effects from CFTR modulation were those patients with one gating mutation receiving IVA (ivacaftor) and patients with p.Phe508del mutation, both homozygous and heterozygous, receiving ELX/TEZ/IVA (elexacaftor/tezacaftor/ivacaftor) had the most relevant beneficial effects in term of lung function, pulmonary exacerbation decrease, and symptom improvement. CFTR modulators showed an overall favorable safety profile. Next steps should aim to systematize our comprehension of scientific data of efficacy and safety coming from real life observational studie

SOCS2-Induced Proteasome-Dependent TRAF6 Degradation: A Common Anti-Inflammatory Pathway for Control of Innate Immune Responses

Pattern recognition receptors and receptors for pro-inflammatory cytokines provide critical signals to drive the development of protective immunity to infection. Therefore, counter-regulatory pathways are required to ensure that overwhelming inflammation harm host tissues. Previously, we showed that lipoxins modulate immune response during infection, restraining inflammation during infectious diseases in an Aryl hydrocarbon receptor (AhR)/suppressors of cytokine signaling (SOCS)2-dependent-manner. Recently, Indoleamine-pyrrole 2,3- dioxygenase (IDO)-derived tryptophan metabolites, including L-kynurenine, were also shown to be involved in several counter-regulatory mechanisms. Herein, we addressed whether the intracellular molecular events induced by lipoxins mediating control of innate immune signaling are part of a common regulatory pathway also shared by L-kynurenine exposure. We demonstrate that Tumor necrosis factor receptor-associated factor (TRAF)6 – member of a family of adapter molecules that couple the TNF receptor and interleukin-1 receptor/Toll-like receptor families to intracellular signaling events essential for the development of immune responses – is targeted by both lipoxins and L-kynurenine via an AhR/SOCS2-dependent pathway. Furthermore, we show that LXA4- and L-kynurenine-induced AhR activation, its subsequent nuclear translocation, leading SOCS2 expression and TRAF6 Lys47-linked poly-ubiquitination and proteosome-mediated degradation of the adapter proteins. The in vitro consequences of such molecular interactions included inhibition of TLR- and cytokine receptor-driven signal transduction and cytokine production. Subsequently, in vivo proteosome inhibition led to unresponsiveness to lipoxins, as well as to uncontrolled pro-inflammatory reactions and elevated mortality during toxoplasmosis. In summary, our results establish proteasome degradation of TRAF6 as a key molecular target for the anti-inflammatory pathway triggered by lipoxins and L-kynurenine, critical counter-regulatory mediators in the innate and adaptive immune systems