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Hepatocellular carcinoma (HCC) accounts for over 80% of liver cancer cases and is highly malignant, recurrent, drug-resistant, and often diagnosed in the advanced stage. It is clear that early diagnosis and a better understanding of molecular mechanisms contributing to HCC progression is clinically urgent. Metabolic alterations clearly characterize HCC tumors. Numerous clinical parameters currently used to assess liver functions reflect changes in both enzyme activity and metabolites. Indeed, differences in glucose and acetate utilization are used as a valid clinical tool for stratifying patients with HCC. Moreover, increased serum lactate can distinguish HCC from normal subjects, and serum lactate dehydrogenase is used as a prognostic indicator for HCC patients under therapy. Currently, the emerging field of metabolomics that allows metabolite analysis in biological fluids is a powerful method for discovering new biomarkers. Several metabolic targets have been identified by metabolomics approaches, and these could be used as biomarkers in HCC. Moreover, the integration of different omics approaches could provide useful information on the metabolic pathways at the systems level. In this review, we provided an overview of the metabolic characteristics of HCC considering also the reciprocal influences between the metabolism of cancer cells and their microenvironment. Moreover, we also highlighted the interaction between hepatic metabolite production and their serum revelations through metabolomics researches.

Background Biliary tract cancers (BTCs) are rare and lethal cancers, with a 5-year survival inferior to 20%(1–3). The only potential curative treatment is surgical resection. However, despite complex surgical procedures that have a remarkable risk of postoperative morbidity and mortality, the 5-year survival rate after radical surgery (R0) is 20–40% and recurrence rates are up to ~ 75%(4–6). Up to ~ 40% of patients relapse within 12 months after resection, and half of these patient will recur systemically(4–6). There is no standard of care for neoadjuvant chemotherapy (NAC) in resectable BTC, but retrospective reports suggest its potential benefit (7, 8). Methods PURITY is a no-profit, multicentre, randomized phase II/III trial aimed at evaluating the efficacy of the combination of gemcitabine, cisplatin and nabpaclitaxel (GAP) as neoadjuvant treatment in patients with resectable BTC at high risk for recurrence. Primary objective of this study is to evaluate the efficacy of neoadjuvant GAP followed by surgery as compared to upfront surgery, in terms of 12-month progression-free survival for the phase II part and of progression free survival (PFS) for the phase III study. Key Secondary objectives are event free survival (EFS), relapse-free survival, (RFS), overall survival (OS), R0/R1/R2 resection rate, quality of life (QoL), overall response rate (ORR), resectability. Safety analyses will include toxicity rate and perioperative morbidity and mortality rate. Exploratory studies including Next-Generation Sequencing (NGS) in archival tumor tissues and longitudinal ctDNA analysis are planned to identify potential biomarkers of primary resistance and prognosis. Discussion Considering the poor prognosis of resected BTC experiencing early tumor recurrence and the negative prognostic impact of R1/R2 resections, PURITY study is based on the rationale that NAC may improve R0 resection rates and ultimately patients’ outcomes. Furthermore, NAC should allow early eradication of microscopic distant metastases, undetectable by imaging but already present at the time of diagnosis and avoid mortality and morbidity associated with resection for patients with rapid progression or worsening general condition during neoadjuvant therapy. The randomized PURITY study will evaluate whether patients affected by BTC at high risk from recurrence benefit from a neoadjuvant therapy with GAP regimen as compared to immediate surgery. Trial registration PURITY is registered at ClinicalTrials.gov (NCT06037980) and EuCT(2023–503295-25–00).

Bevacizumab (B) plus chemotherapy (CT) is a common choice for first-line treatment of metastatic colorectal cancer. Molecular predictors of B efficacy have still not been identified. We analyzed the role of 22 angiogenesis-associated proteins in patient outcome. Serum samples collected at baseline and at the first clinical evaluation were available for 58 patients enrolled in the randomized multicenter trial and who received CT+ B. Serum protein levels were determined using multiplex ELISA. Patients with baseline ≥145 pg/mL IL-8 showed shorter median progression-free survival and overall survival (OS) than those with lower levels (6.5 vs 6. 12.6 months; HR 7.39, <0.0001 and 8.7 vs 28.8 months, HR 7.68, <0.001, respectively). Moreover, patients with baseline thrombospondin-1 levels ≥12,000 ng/mL had a better median OS than those with lower levels (34.5 vs 13.1 months, HR 0.43, =0.007). Patients with a ≥20% reduction in IL-8 levels from baseline to first clinical evaluation showed a better progression-free survival and OS than the others (HR 0.41, =0.005 and HR 0.43, =0.007, respectively). Baseline IL-8 and thrombospondin-1 levels and reduced IL-8 during B treatment could represent potential prognostic markers in metastatic colorectal cancer.

The aim of this study was to investigate the role of pre-treatment aspartate aminotransferase-lynphocyte ratio (ALRI) as a predictor of prognosis and treatment efficacy in patients with metastatic colorectal cancer (mCRC) enrolled in the prospective multicenter randomized ITACa (Italian Trial in Advanced Colorectal Cancer) trial to receive first-line chemotherapy (CT) + bevacizumab (B) or CT alone. Patients randomly received CT+B or CT alone as first-line therapy. CT consisted of either FOLFOX4 or FOLFIRI at the clinician's discretion. Out of the 284 patients enrolled, increased ALRI levels were associated with shorter PFS and OS ( <0.0001). At baseline, median PFS was 10.3 months (95% CI 9.4-12.0) and 8.0 months (95 % CI 6.8-8.9), and median OS was 25.2 months (95 % CI 21.3-30.2) and 18.8 months (95 % CI 16.6-21.7) for patients with low (<14) and high (≥14) ALRI levels, respectively (HR 1.43, 95% CI 1.12-1.82, =0.004; HR=1.51, 95% CI 1.17-1.96, <0.001). Interaction tests on ALRI levels and treatment efficacy in the CT+B and the CT groups were statistically significant for PFS ( =0.0003), but not for OS ( =0.228). Our results indicate that ALRI is a good prognostic and predictive marker for mCRC patients candidate for CT+B.

The sulfated glycosaminoglycan heparin is the most commonly used pharmaceutical anticoagulant worldwide. Heparin, which is extracted primarily from porcine sources, has a complex heterogeneous structure, resulting in a highly variable pharmaceutical product susceptible to contamination. As a by-product of the food industry, heparin is also limited by production capacity, giving rise to concerns that demand will outstrip supply. The anticoagulant activity of heparin derives principally from the AGA*IA pentasaccharide sequence, containing a rare 3-O-sulfated glucosamine, which binds and activates antithrombin. Analytical heparin digestion by the widely used Pedobacter heparinus lyases has limited activity in regions of 3-O-sulfation, rendering these enzymes poorly suited to study anticoagulant sequences. Here, we provide structural and functional characterization of a Bacteroides eggerthii lyase that exhibits highly efficient heparin depolymerization, with specificity distinct to P. heparinus. Using a panel of biophysical and structural techniques, we demonstrate that B. eggerthii lyase effectively liberates the rare GA* disaccharide, a key indicator of anticoagulant potential, from the defined heparin pentasaccharide fondaparinux. We envision superior cleavage by B. eggerthii lyases will enable the future quantitative, direct detection of anticoagulant relevant 3-O-sulfated sequences, delivering complementary structural information to existing analytical methods, with clear utility for pharmaceutical quality control workflows.

Neogene strain from the subducting Nazca plate is widely distributed in theAndean foreland as a result of flat-lying subduction beneath central westernArgentina (28^sup °^-33^sup °^S latitude). This fact is indicated byuplifted basement blocks bounded by reverse faults as far as 600 kms eastof the Chilean trench axis. Some deformation in the southern Sierras deCórdoba (southeastern Sierras Pampeanas) indicates significantdisplacements during Quaternary and even late Holocene time. Thisregion has low to moderate seismicity characterized by earthquakemagnitudes ≤ 6.7 with no associated noticeable surface ruptures.This paper presents information recently gathered on the most conspicuousregional structures of the area (El Molino, Sierra Chica and Las Lagunasfaults). The last movement along the El Molino fault thrust basement rocksover organic-rich (0.8-1.3 ka) sediment and fault relationships suggestprevious Quaternary displacements. Along the Sierra Chica fault,Precambrian basement has been thrust a minimum of 13.5 m overPleistocene conglomerates, and faulting also affects latePleistocene-Holocene fluvial sediments. The Las Lagunas fault has beenregarded as the source of the 1934 Ms 5.5 and 6.0 earthquakes, whichheavily damaged the nearby village of Sampacho. The faulted surface isburied under Holocene loess, but its trace is expressed as a 24-km-longrectilinear scarp, despite continuous modification due to land use.Although we lack detailed information on probable rupture lengths duringlarge Sierras Pampeanas thrust earthquakes, some preliminary considerationsare made for the regional seismic hazard of these structures. The geologicevidence described here identifies these faults as possible sources of strongearthquakes in the future.[PUBLICATION ABSTRACT]

The Peruvian amazon is very diverse in native forestry species, the Guazuma crinita “Bolaina” being one of the most planted species in the country; however, little or no information about soil requirements and nutrient demands is known. The objective of this work was to assess the general conditions of soil fertility, biomass and macro- and micronutrient amounts in high-productivity Guazuma crinita plantations. Fields of high yielding Bolaina of different ages (1–10 years) were sampled in two regions. Soil and plant samples were collected in each field and biometric measurements of fresh weight, diameter at breast height and height were performed. For soil and plant analysis, both macro- (N, P, K, Ca, Mg, S) and micronutrients (B, Cu, Fe, Mn, Zn) were determined. Finally, allometric equations were constructed for biometric and nutrient amounts. This study is the first to assess and model macro- and micronutrient amounts in the productive cycle in this species, which grows in fertile soils. In the case of biometric equations, the logarithmic and logistic models performed better. For nutrient amounts, this species followed a pattern of Ca > N > K > P > S > Mg for macronutrients and Fe > B > Mn > Zn > Cu for micronutrients. The best prediction models for nutrients were the square root and logistic models.

α-catenin is a crucial protein at cell junctions that provides connection between the actin cytoskeleton and the cell membrane. At adherens junctions (AJs), α-catenin forms heterodimers with β-catenin that are believed to resist force on F-actin. Outside AJs, α-catenin forms homodimers that regulates F-actin organization and directly connect the cell membrane to the actin cytoskeleton, but their mechanosensitive properties are inherently unknown. By using ultra-fast laser tweezers we found that a single α-β-catenin heterodimer does not resist force but instead slips along F-actin in the direction of force. Conversely, the action of 5 to 10 α-β-catenin heterodimers together with force applied toward F-actin pointed end engaged a molecular switch in α-catenin, which unfolded and strongly bound F-actin as a cooperative catch bond. Similarly, an α-catenin homodimer formed an asymmetric catch bond with F-actin triggered by protein unfolding under force. Our data suggest that α-catenin clustering together with intracellular tension engage a fluid-to-solid phase transition at the membrane-cytoskeleton interface. By using laser tweezers, the authors show that a single α-catenin molecule does not resist force on F-actin. However, clustering of multiple molecules and force applied toward F-actin pointed end engage a molecular switch in α-catenin, which unfolds and strongly binds F-actin.

Bacterial biofilms are highly complex communities in which isogenic bacteria display different gene expression patterns and organize in a three-dimensional mesh gaining enhanced resistance to biocides. The molecular mechanisms behind such increased resistance remain mostly unknown, also because of the technical difficulties in biofilm investigation at the sub-cellular and molecular level. In this work we focus on the AcrAB-TolC protein complex, a multidrug efflux pump found in Enterobacteriaceae, whose overexpression is associated with most multiple drug resistance (MDR) phenotypes occurring in Gram-negative bacteria. We propose an optical method to quantify the expression level of the AcrAB-TolC pump within the biofilm volume at the sub-cellular level, with single-molecule sensitivity. Through a combination of super-resolution PALM with single objective light sheet and precision genome editing, we can directly quantify the spatial distribution of endogenous AcrAB-TolC pumps expressed in both planktonic bacteria and, importantly, within the bacterial biofilm volume. We observe a gradient of pump density within the biofilm volume and over the course of biofilm maturation. Notably, we propose an optical method that could be broadly employed to achieve volumetric super-resolution imaging of thick samples.