Search

Abstract Background Breast cancer manifests as a heterogeneous pathology marked by complex metabolic reprogramming essential to satisfy its energy demands. Oncogenic signals boost the metabolism, modifying fatty acid synthesis and glucose use from the onset to progression and therapy resistant-forms. However, the exact contribution of metabolic dependencies during tumor evolution remains unclear. Methods In this study, we elucidate the connection between FASN and LDHA, pivotal metabolic genes, and their correlation with tumor grade and therapy response using datasets from public repositories. Subsequently, we evaluated the metabolic and proliferative functions upon FASN and LDHA inhibition in breast cancer models. Lastly, we integrated metabolomic and lipidomic analysis to define the contributions of metabolites, lipids, and precursors to the metabolic phenotypes. Results Collectively, our findings indicate metabolic shifts during breast cancer progression, unvealling two distinct functional energy phenotypes associated with aggressiveness and therapy response. Specifically, FASN exhibits reduced expression in advance-grade tumors and therapy-resistant forms, whereas LDHA demonstrates higher expression. Additionally, the biological and metabolic impact of blocking the enzymatic activity of FASN and LDHA was correlated with resistant conditions. Conclusions These observations emphasize the intrinsic metabolic heterogeneity within breast cancer, thereby highlighting the relevance of metabolic interventions in the field of precision medicine.

Abstract Osimertinib is a third-generation tyrosine kinase inhibitor clinically approved for first-line treatment of EGFR-mutant non-small cell lung cancer (NSCLC) patients. Although an impressive drug response is initially observed, in most of tumors, resistance occurs after different time and an alternative therapeutic strategy to induce regression disease is currently lacking. The hyperactivation of MEK/MAPKs, is one the most common event identified in osimertinib-resistant (OR) NSCLC cells. However, in response to selective drug pressure, the occurrence of multiple mechanisms of resistance may contribute to treatment failure. In particular, the epithelial-to-mesenchymal transition (EMT) and the impaired DNA damage repair (DDR) pathways are recognized as additional cause of resistance in NSCLC thus promoting tumor progression. Here we showed that concurrent upregulation of ITGB1 and DDR family proteins may be associated with an increase of EMT pathways and linked to both osimertinib and MEK inhibitor resistance to cell death. Furthermore, this study demonstrated the existence of an interplay between ITGB1 and DDR and highlighted, for the first time, that combined treatment of MEK inhibitor with DDRi may be relevant to downregulate ITGB1 levels and increase cell death in OR NSCLC cells.

Geodemographic classifications are an important tool to support public-service decision making. While people are the focal point of geodemographics, classifications are often built on variables that describe populations rather than individuals. Synthetic populations, model-based approximations of the individual makeup of small census areas, remain largely unused for geodemographic classification, yet they can provide a more direct and holistic understanding of localized resource needs than existing approaches. This paper develops a new method for performing individual-centered geodemographic classifications using synthetic populations. The building blocks of this approach are abstractions of the synthetic population attributed to each small census area via affinity matrices computed from similarities in both the size and attributes among individuals. Using a rank-1 spectral decomposition of an area’s affinity matrix enables rapid computation of a dissimilarity metric which is compatible with cluster analysis techniques used in traditional geodemographic classifications. Using data from the American Community Survey (ACS), an example classification is developed for the Knoxville, TN, USA Public-Use Microdata Area (PUMA) to illustrate how distinctions can be drawn among small census areas in terms of specific types of representative individuals, providing a more tailored view of the groups that serve to benefit from spatial policy interventions. Beyond improving traditional public-domain geodemographic classifications, this approach provides a novel open-source alternative to commercial neighborhood segmentation products with added flexibility for custom research applications.

Sourdough technology has been known for its role in the improvement of texture, flavor, and quality of mainly wheat and rye-based breads for decades. However, little is reported about its use in the improvement of whole-grain oat bread, especially concerning flavor formation, which is one major consumer drivers. This study investigated the effects of sourdough obtained by different lactic acid bacteria and yeast starters consortia on the texture and flavor of 100% oat bread. Four different consortia were selected to obtain four oat sourdoughs, which were analyzed to assess the main features due to the different starter fermentation metabolism. Sourdoughs were added to breads as 30% dough weight. Bread quality was technologically monitored via hardness and volume measurements. Sourdough breads were softer and had higher specific volume. The sensory profile of sourdoughs and breads was assessed by a trained panel in sensory laboratory conditions, and the volatile profile was analyzed by HS-SPME-GC-MS. Sourdoughs were rated with higher intensities than untreated control for most of attributes, especially concerning sour aroma and flavor attributes. Sourdough breads were rated with higher intensities than control bread for sour vinegar flavor and total odor intensity, in addition they had richer volatile profile. Our results confirmed that sourdough addition can lead to an enhanced flavor, moreover, it demonstrated that the use of different consortia of lactic acid bacteria and yeast strains leads to the improvement of texture and altered sensory profile of whole-oat bread.

IntroductionThe use of contemporary drug-eluting stents (DES) has significantly improved outcomes of patients with coronary artery disease (CAD) undergoing percutaneous coronary intervention (PCI). However, concerns exist regarding the long-term proinflammatory effects of durable polymer coatings used in most DES, potentially leading to long-term adverse events. First-generation polymer-free stent technologies, such as sirolimus- and probucol-eluting stents (PF-SES), have shown an excellent safety and efficacy profile. The aim of this study was to evaluate the safety and efficacy of the new ultrathin Coroflex ISAR NEO PF-SES, in a more-comers PCI population.MethodsThe CAESAR (a more-Comers populAtion trEated with an ultrathin struts polimer-free Sirolimus stent: An Italian post-maRketing study) registry is a multicenter, prospective study conducted in Italy, enrolling more-comers CAD patients undergoing PCI with the Coroflex ISAR NEO stent. Patients with left main (LM) disease, cardiogenic shock (CS), or severely reduced left-ventricular ejection fraction (LVEF) were excluded. The primary endpoint was target-lesion revascularization (TLR) at 1 year.ResultsA total of 425 patients were enrolled at 13 centers (mean age 66.9 ± 11.6 years, Diabetes mellitus 29%, acute coronary syndrome 67%, chronic total occlusion 9%). Of these, 40.9% had multivessel disease (MVD) and in 3.3% cases, the target lesion was in-stent restenosis (ISR). Clinical device success was reached in 422 (99.6%) cases. At 1 year, only two (0.5%) subjects presented ischemia-driven TLR. The 1-year rates of target vessel revascularization and MACE were 0.5% and 5.1%, respectively. Major bleeding was observed in four (1.0%) patients.ConclusionIn this multicenter, prospective registry, the use of a new ultrathin Coroflex ISAR NEO PF-SES in a more-comers PCI population showed good safety and efficacy at 1 year.

Telomerase activity and telomere elongation are essential conditions for the unlimited proliferation of neoplastic cells. Point mutations in the core promoter region of the telomerase reverse transcriptase (TERT) gene have been found to occur at high frequencies in several tumour types and considered a primary cause of telomerase reactivation in cancer cells. These mutations promote TERT gene expression by multiple mechanisms, including the generation of novel binding sites for nuclear transcription factors, displacement of negative regulators from DNA G-quadruplexes, recruitment of epigenetic activators and disruption of long-range interactions between TERT locus and telomeres. Furthermore, TERT promoter mutations cooperate with TPP1 promoter nucleotide changes to lengthen telomeres and with mutated BRAF and FGFR3 oncoproteins to enhance oncogenic signalling in cancer cells. TERT promoter mutations have been recognized as an early marker of tumour development or a major indicator of poor outcome and reduced patients survival in several cancer types. In this review, we summarize recent findings on the role of TERT promoter mutations, telomerase expression and telomeres elongation in cancer development, their clinical significance and therapeutic opportunities.

Background: Lung cancer (LC), including both non-small (NSCLC) and small (SCLC) subtypes, is currently treated with a combination of chemo- and immunotherapy. However, predictive biomarkers to identify high-risk patients are needed. Here, we explore the role of peripheral blood mononuclear cells (PBMCs) as a tool for novel biomarkers searching. Methods: We analyzed the expression of the cGAS-STING pathway, a key DNA sensor that activates during chemotherapy, in PBMCs from LC patients divided into best responders (BR), responders (R) and non-responders (NR). The PBMCs were whole exome sequenced (WES). Results: PBMCs from BR and R patients of LC cohorts showed the highest levels of STING (p < 0.0001) and CXCL10 (p < 0.0001). From WES, each subject had at least 1 germline/somatic alteration in a DDR gene and the presence of more DDR gene mutations correlated with clinical responses, suggesting novel biomarker implications. Thus, we tested the effect of the pharmacological DDR inhibitor (DDRi) in PBMCs and in three-dimensional spheroid co-culture of PBMCs and LC cell lines; we found that DDRi strongly increased cGAS-STING expression and tumor infiltration ability of immune cells in NR and R patients. Furthermore, we performed FACS analysis of PBMCs derived from LC patients from the BR, R and NR cohorts and we found that cytotoxic T cell subpopulations displayed the highest STING expression. Conclusions: cGAS-STING signaling activation in PBMCs may be a novel potential predictive biomarker for the response to immunotherapy and high levels are correlated with a better response to treatment along with an overall increased antitumor immune injury.

Legumes have been recognised as healthy and environmentally friendly protein sources. Knowledge about the vitamin B contents in legume ingredients and extrudates is scarce. In this study, we investigated thiamin, riboflavin, niacin, and folate in various faba bean, lupin, and pea ingredients. Further, the retention of B vitamins in high moisture extrusion was studied. Prior to liquid chromatographic determinations of thiamin, riboflavin, niacin, and folate, vitamins were extracted by acid hydrolysis (niacin), enzymatic treatment (folate), or their combination (thiamin and riboflavin). The contents (on a dry matter basis) varied greatly among different ingredients: the thiamin content was 0.2–14.2 µg/g; riboflavin, 0.3–5.9 µg/g; niacin, 8.8–35.5 µg/g, and folate, 45–1453 ng/g. Generally, the highest levels were in flours and protein concentrates, whereas low levels were observed in isolates. The retention of B vitamins was excellent in high moisture extrusion, except for folate in faba bean, where the folate contents were 42–67% lower in the extrudates than in the respective ingredient mixtures. In terms of both vitamin B contents and their retention, extrudates containing substantial amounts of flour or protein concentrate are promising plant-based sources of thiamin, riboflavin, niacin, and folate.

Abstract Climate change has led to an increase in heat‐related morbidity and mortality. The impact of heat on health is unequally distributed amongst different socioeconomic and demographic groups. We use high‐resolution daily air temperature‐based heat wave intensity (HWI) and neighborhood‐scale sociodemographic information from the conterminous United States to evaluate the spatial patterning of extreme heat exposure disparities. Assuming differences in spatial patterns at national, regional, and local scales; we assess disparities in heat exposure across race, housing characteristics, and poverty level. Our findings indicate small differences in HWI based on these factors at the national level, with the magnitude and direction of the differences varying by region. The starkest differences are present over the Northeast and Midwest, where primarily Black neighborhoods are exposed to higher HWI than predominantly White areas. At the local level, we find the largest difference by socioeconomic status. We also find that residents of nontraditional housing are more vulnerable to heat exposure. Previous studies have either evaluated such disparities for specific cities and/or used a satellite‐based land surface temperature, which, although correlated with air temperature, does not provide the true measure of heat exposure. This study is the first of its kind to incorporate high‐resolution gridded air temperature–based heat exposure in the evaluation of sociodemographic disparities at a national scale. The analysis suggests the unequal distribution of heat wave intensities across communities—with higher heat exposures characterizing areas with high proportions of minorities, low socioeconomic status, and homes in need of retrofitting to combat climate change.

Il presente lavoro esamina le conseguenze della risoluzione per inadempimento di un contratto di leasing traslativo affrontando le questioni dell’efficacia intertemporale delle disposizioni della legge 124/2017 e della validità del patto di deduzione alla luce delle ultime pronunce della Cassazione. Prosegue, infine, con una breve indagine sulla natura della somma dovuta ai sensi dell’art. 1 comma 138 della legge 124/2017, in particolare sulla possibilità di rinvenire nella stessa una funzione compensativa; nonché sul rischio che la suddetta disciplina (e, a maggior ragione quella in materia di leasing immobiliare abitativo) possa costituire un mezzo per disciogliersi dal divieto del patto commissorio, che opera invece in materia di mutuo. This paper examines the consequences of the termination for non-performance of a transfer lease by addressing the issues of the intertemporal effectiveness of the provisions of Law 124/2017 and the validity of the deduction covenant in light of the latest rulings of the Supreme Court. Finally, it continues with a brief investigation on the nature of the sum due pursuant to Article 1 paragraph 138 of Law 124/2017, in particular on the possibility of finding in it a compensatory function; as well as on the risk that the aforesaid rules (and, a fortiori, those on residential real estate leasing) may constitute a means of disengaging from the prohibition of the covenant of commission, which instead operates in the matter of mortgages.

Rare endocrine conditions present specific diagnostic and manage ment challenges for healthcare providers, one of which is the understudied transition of care. Despite the need for guidance regarding transition, consensus on structured and protocolled approaches is lacking. Therefore, we aimed to map the current clinical practice and identify unmet needs regarding transition of care for patients with pituitary disease in the reference centers (RCs) of the European Reference Network on Rare Endocrine Conditions (Endo-ERN). A survey-based, cross-sectional study using the EU Survey tool was performed and completed by 46 physicians (n) from 30 RCs (N). Transition is a common practice among RCs (n = 44/46), usually accomplished by a multidisciplinary team meeting (N = 20/30). Criteria for start and end of transition were defined in half of the RCs, with 16.7% of centers providing dissimilar answers. Transition readiness was assessed by >75% of the RCs, mostly by unvalidated means (e.g. subjective opinions, informal consultations). Pituitary-specific transition assessment tool was applied in one RC only. Transition protocols were present in only 9% of RCs, while in many RCs, tr ansition decisions were taken in combined adult-pediatric meetings or based on clinicians’ personal judgment. A minority of physicians evaluated the effectiveness of transiti on-related interventions (n = 11/46) or medical outcomes (n = 8/46). Patient-reported outcome measures were infrequently used (n = 4/46). Identified unmet needs included the development of guidelines (n = 5/46) and EU-wide approach (n = 2/46). This study exemplifies the unmet needs for a structural definition of the transition period and t ransition management for patients with rare hypothalamic and pituitary conditions from healthcare providers’ perspective.

Abstract Background Chronic obstructive pulmonary disease (COPD) is projected to become the third cause of mortality worldwide. COPD shares several pathophysiological mechanisms with cardiovascular disease, especially atherosclerosis. However, no definite answers are available on the prognostic role of COPD in the setting of ST elevation myocardial infarction (STEMI), especially during COVID-19 pandemic, among patients undergoing primary angioplasty, that is therefore the aim of the current study. Methods In the ISACS-STEMI COVID-19 registry we included retrospectively patients with STEMI treated with primary percutaneous coronary intervention (PCI) between March and June of 2019 and 2020 from 109 high-volume primary PCI centers in 4 continents. Results A total of 15,686 patients were included in this analysis. Of them, 810 (5.2%) subjects had a COPD diagnosis. They were more often elderly and with a more pronounced cardiovascular risk profile. No preminent procedural dissimilarities were noticed except for a lower proportion of dual antiplatelet therapy at discharge among COPD patients (98.9% vs. 98.1%, P = 0.038). With regards to short-term fatal outcomes, both in-hospital and 30-days mortality occurred more frequently among COPD patients, similarly in pre-COVID-19 and COVID-19 era. However, after adjustment for main baseline differences, COPD did not result as independent predictor for in-hospital death (adjusted OR [95% CI] = 0.913[0.658–1.266], P = 0.585) nor for 30-days mortality (adjusted OR [95% CI] = 0.850 [0.620–1.164], P = 0.310). No significant differences were detected in terms of SARS-CoV-2 positivity between the two groups. Conclusion This is one of the largest studies investigating characteristics and outcome of COPD patients with STEMI undergoing primary angioplasty, especially during COVID pandemic. COPD was associated with significantly higher rates of in-hospital and 30-days mortality. However, this association disappeared after adjustment for baseline characteristics. Furthermore, COPD did not significantly affect SARS-CoV-2 positivity. Trial registration number: NCT 04412655 (2nd June 2020).

Hericium erinaceus, berberine, and quercetin are effective in experimental colitis. It is unknown whether they can ameliorate inflammatory bowel diseases in humans. This ex vivo study aimed to evaluate the anti-inflammatory potential of a nutraceutical compound of HBQ-Complex® (H. erinaceus, berberine, and quercetin), biotin, and niacin in inflammatory bowel disease patients. Tissue specimens were obtained either from Normal-Appearing Mucosa (NAM) or from Inflamed Mucosa (IM) in 20 patients with inflammatory bowel disease. mRNA and protein expression of COX-2, IL-10, and TNF-α were determined in NAM and IM biopsy samples (T0). IM samples were then incubated in HBQ-Complex® (with the addition of niacin and biotin), and COX-2, IL-10, and TNF-α tissue levels were evaluated at 120 minutes (T1) and 180 minutes (T2). Incubation with this compound resulted in a progressive decrease in gene and protein COX-2 and TNF-α expression at T1/T2 in the IM. IL-10 showed an opposite trend, with a progressive increase of mRNA and protein expression over the same time window. HBQ-Complex® (with the addition of niacin and biotin) decreased the expression of proinflammatory cytokines at the mRNA and protein levels in IBD tissue. On the contrary, mRNA and protein expression of the anti-inflammatory cytokine IL-10 showed a progressive increase.

Background. Since the European Society of Cardiology (ESC) published guidelines to stratify the risk of pulmonary embolism (PE), the main goal of several physicians has been to find a biomarker able to identify patients with venous thromboembolism at high risk to die. Increased levels of pro-B-type natriuretic peptide (BNP) were suggested as useful biomarkers in the guidelines of ESC (i.e., 2014) to identify patients with PE at high risk of death, but its role was not confirmed in other guidelines. Lung Ultrasound Scan (LUS) has been suggested as a diagnostic and prognostic test to identify patients with a high risk of mortality for lung failure. The aim of this study is to evaluate the prognostic role of pro- BNP together with the LUS evaluation in patients with COVID-19 and PE in particular regarding mortality for pulmonary embolism and overall death. Patients and Methods. We retrospectively analyzed records from 178 patients with confirmed COVID-19, admitted to our ward (i.e., COVID Medicine Unit at Ospedale del Mare in the town of Napoli) between March 2020 and May 2021. For this study, we analyzed the LUS data of all 178 patients and the available data on the pro-BNP of 120 patients. For all selected patients, mortality for PE and overall deaths were recorded. Results. The Propensity Score Matching was used to minimize and erase confounding factors. Data showed that an association between serum levels of pro-BNP and pulmonary thrombotic events was neither present before nor after matching an association with adverse outcomes and was found for increased values of LUS. Discussion. During the first waves of the pandemic, patients with confirmed COVID-19 with severe lung failure frequently showed pulmonary embolism as a clinical acute complication inducing life-threatening evolution. Conclusions. An association between LUS score and severe PE and/or overall mortality in hospitalized patients with COVID-19 was found while a similar association was not confirmed for pro-BNP.

Globally, lead (Pb) contamination is one of the top ten chemical exposure issues affecting public health. The identification of specific Pb sources provides valuable information to determine assignment of liability for site cleanup, improve sampling plans and develop remedial strategies. This paper examines Pb concentrations and Pb isotopic data from samples collected at and near the site of a Pb paint production facility with a long operating history. Although high soil Pb concentrations were found at the site, Pb concentrations in surrounding neighborhoods did not simply decline with distance from the site. We evaluated soil concentrations and isotopic mixing lines to explore potential sources of Pb pollution. Three-isotope plots showed overlap of site samples and the surrounding neighborhood, consistent with pollution from the facility affecting offsite soils. A major challenge in separation of potential sources, however, is that the isotopic signatures of other potential Pb sources fall within the range of the soil data. The long operational site history, soil disturbances, the presence of nearby smelters, and other local and remote sources affect identification of lead sources. This analysis demonstrates that source attribution can be confounded by incomplete site and material sourcing information. An integrated approach that includes in-depth site characterization and an evaluation of historical activities (e.g., Pb ores used over time, amounts of Pb emitted by all area smelters, land use changes, and soil disturbances) is important for determining source attribution. This analysis provides insight into future site investigations where soil lead contamination has resulted from a long industrial history in an urban setting.

Since the last IAEA-FEC in 2021, significant progress on the development of long pulse steady state scenario and its related key physics and technologies have been achieved, including the reproducible 403 s long-pulse steady-state H-mode plasma with pure radio frequency (RF) power heating. A thousand-second time scale (∼1056 s) fully non-inductive plasma with high injected energy up to 1.73 GJ has also been achieved. The EAST operational regime of high β _P has been significantly extended ( H _98y2 > 1.3, β _P ∼ 4.0, β _N ∼ 2.4 and n _e / n _GW ∼ 1.0) using RF and neutral beam injection (NBI). The full edge localized mode suppression using the n = 4 resonant magnetic perturbations has been achieved in ITER-like standard type-I ELMy H-mode plasmas with q _95 ≈ 3.1 on EAST, extrapolating favorably to the ITER baseline scenario. The sustained large ELM control and stable partial detachment have been achieved with Ne seeding. The underlying physics of plasma-beta effect for error field penetration, where toroidal effect dominates, is disclosed by comparing the results in cylindrical theory and MARS-Q simulation in EAST. Breakdown and plasma initiation at low toroidal electric fields (