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Abstract Pancreatic Ductal Adenocarcinoma (PDAC) has a five-year survival under 10%. Treatment is compromised due to a fibrotic-like stromal remodeling process, known as desmoplasia, which limits therapeutic perfusion, supports tumor progression, and establishes an immunosuppressive microenvironment. These processes are driven by cancer-associated fibroblasts (CAFs), functionally activated through transforming growth factor beta1 (TGFβ1). CAFs produce a topographically aligned extracellular matrix (ECM) that correlates with reduced overall survival. Paradoxically, ablation of CAF populations results in a more aggressive disease, suggesting CAFs can also restrain PDAC progression. Thus, unraveling the mechanism(s) underlying CAF functions could lead to therapies that reinstate the tumor-suppressive features of the pancreatic stroma. CAF activation involves the f-actin organizing protein palladin. CAFs express two palladin isoforms (iso3 and iso4) which are up-regulated in response to TGFβ1. However, the roles of iso3 and iso4 in CAF functions remain elusive. Using a CAF-derived ECM model, we uncovered that iso3/iso4 are required to sustain TGFβ1-dependent CAF activation, secrete immunosuppressive cytokines, and produce a pro-tumoral ECM. Findings demonstrate a novel role for CAF palladin and suggest that iso3/iso4 regulate both redundant and specific tumor-supportive desmoplastic functions. This study highlights the therapeutic potential of targeting CAFs to restore fibroblastic anti-tumor activity in the pancreatic microenvironment.

Abstract Bruton’s tyrosine kinase (BTK), expressed in B cells and cells of innate immunity, including microglia, is an essential signaling element downstream of the B‐cell receptor and Fc‐receptors. Tolebrutinib (PRN2246, SAR442168) is a potent BTK inhibitor that covalently binds the kinase, resulting in durable inhibition with the potential to target inflammation in the periphery and central nervous system (CNS). Tolebrutinib crosses the blood‐brain barrier and potently inhibits BTK in microglial cells isolated from the CNS. A first‐in‐human randomized, double‐blind, placebo‐controlled study of tolebrutinib was conducted. The trial design consisted of five single ascending dose arms with oral administration of a single dose of 5, 15, 30, 60, and 120 mg (n = 6 per arm, n = 2 placebo), five multiple ascending dose arms with oral administration of 7.5, 15, 30, 60, and 90 mg (n = 8 per arm, n = 2 placebo) over 10 days, and one arm (n = 4) in which cerebral spinal fluid (CSF) exposure was measured 2 h after a single 120 mg dose. Tolebrutinib was well‐tolerated in the study and all treatment‐related treatment emergent adverse events were mild. Tolebrutinib was rapidly absorbed following oral administration with a rapid half‐life of ~ 2 h. Peripheral BTK occupancy was assessed at various timepoints by an enzyme‐linked immunosorbent assay‐based readout using an irreversible probe. Assessments demonstrated extensive and prolonged peripheral BTK occupancy at steady‐state with once daily doses as low as 7.5 mg. Further, CSF exposure was demonstrated 2 h after administration at 120 mg.

Objectives: The quality of life in patients undergoing radical cystectomy and urinary diversion is gaining importance. Nowadays a broad consensus about the best urinary diversion does not exist. This study presents an all-round analysis of the impact of two types of urinary diversion on life's psycho-social aspects in patients undergoing radical cystectomy., Methods: This is an observational, single-centre, prospective study. Eligible participants underwent radical cystectomy and urinary diversion for bladder cancer in our department from January 2020 and February 2024. Of 130 included patients, 90 (45 with Bricker's ureteroileocutaneostomy and 45 received orthotopic bladder replacement) patients were matched and the study groups were well balanced for the baseline-matched variables. Patients completed 4 questionnaires (EORTC QLQ-C30, PGWBI, HADS, PSQI) at three different times: before the surgical procedure, and at 3 and 12 months., Results: Time shows a statistically significant effect (p < 0.0005) on four of the five functional scales explored (Physical Functioning, Role Functioning, Emotional Functioning, Social Functioning), and for all the nine symptoms/items' scales (p < 0.0005) and the Global Health Status (p = 0.003) in EORTC QLQ-C30. Neobladder's group shows a statistically significant improvement on the scales of Physical Functioning, Role Functioning, and Social Functioning, and for symptoms of nausea (p = 0.0027), pain (p = 0.0005), dyspnea (p = 0.012), insomnia (p = 0.004), constipation (p = 0.003)., Conclusion: We do not find a better urinary diversion in absolute terms. Neobladder obtained better results only for specific items and features. The urinary diversion's choice must be made in concert by the patient, the caregiver, and health professionals with adequate counseling., (© 2024 The Author(s). International Journal of Urology published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Urological Association.)

In the present work, an analytical method for the quantification of per and poly fluoroalkyl substances (PFAS) in rice and maize has been developed and then validated with a metrological approach. PFAS are a group of human-made chemicals used in a variety of industries and consumer products for their water- and grease-resistant properties. Studies have shown that PFAS can contaminate soil and water, and there is concern about their bioaccumulation in edible plants, fruits, and cereals. The presence of PFAS has been identified in rice and other food products, including maize, as indicated by studies and scientific literature. This is particularly alarming since some PFAS have been associated with adverse health effects and rice and maize account for over 20% of the annual food intake worldwide. Despite this evidence, the regulation currently in place is not covering cereal matrices and limits of quantification for matrices encompassed by the current legislation are defined for a small group of PFAS. In this study an UHPLC-HRMS/MS based method was validated, obtaining a LOQ (Limit Of Quantification) ranging between 2 ng/kg and 32 ng/kg and robustness in line with EU guidelines and recommendation for PFAS in food. Additionally, a metrological approach was employed to estimate the uncertainty budget, utilizing modeling and experimental methods, and comparing the outcomes, aiming to characterize with high accuracy PFAS in rice and maize and support control bodies to assess contamination in suspected areas. A comparison of uncertainty of different approaches was conducted after applying the method to 30 real samples., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: To evaluate PSA value in mp-MRI results prediction, analyzing patients with high (GS≥8, pT≥3, pN1) and low grade (GS<8, pT<3, pN0) Prostate Cancer (PCa)., Materials and Methods: One hundred eighty-eight patients underwent 1.5-Tmp-MRI after Radical Prostatectomy (RP) and before Radiotherapy (RT). They were divided into 2 groups: A and B, for patients with biochemical recurrence (BCR) and without BCR but with high local recurrence risk. Considering Gleason Score (GS), pT and pN as independent grouping variables, ROC analyses of PSA levels at primary PCa diagnosis and PSA before RT were performed in order to identify the optimal cut-off to predict mp-MRI result., Results: Group A and B showed higher AUC for PSA before RT than PSA at PCa diagnosis, in low and high grade tumors. For low grade tumors the best AUC was 0.646 and 0.685 in group A and B; for high grade the best AUC was 0.705 and 1 in group A and B, respectively. For low grade tumors the best PSA cut-off was 0.565-0.58ng/mL in group A (sensitivity, specificity: 70.5%, 66%), and 0.11-0.13ng/mL in B (sensitivity, specificity: 62.5%, 84.6%). For high grade tumors, the best PSA cut-off obtained was 0.265-0.305ng/mL in group A (sensitivity, specificity: 95%, 42.1%), and 0.13-0.15ng/mL in B (sensitivity, specificity: 100%)., Conclusion: Mp-MRI should be performed as added diagnostic tool always when a BCR is detected, especially in high grade PCa. In patients without BCR, mp-MRI results, although poorly related to pathological stadiation, still have a good diagnostic performance, mostly when PSA>0.1-0.15ng/mL., (Copyright © 2023. Published by Elsevier España, S.L.U.)

Portomesenteric vein thrombosis (PMVT) is a rare, life-threatening pathology associated with increased prevalence in laparoscopic sleeve gastrectomy (LSG) versus other gastric bypass procedures. Gaining popularity, LSG is becoming the first choice of patients and physicians alike due to its low complication profile compared to the gastric bypass procedure. We present the case of a 34-year-old woman who underwent an uncomplicated LSG for the treatment of morbid obesity, and presented on postoperative day 13 with PMVT. The patient underwent mechanical thrombectomy and thrombolytic therapy. After 2 days, patency was restored and the patient was discharged in stable condition. A high index of suspicion for PMVT should be considered in patients reporting diffuse abdominal pain after LSG. Owing to its lethality, upon confirmation of PMVT, therapy should begin immediately along with extended anticoagulation therapy on discharge., Competing Interests: Conflicts of Interest: None declared., (2017 BMJ Publishing Group Ltd.)

Purpose: To evaluate the effectiveness and tolerability profile of tapentadol prolonged release (PR) in a cohort of head and neck cancer (HNC) patients affected by background pain due to painful mucositis during intensity modulated radiation therapy with or without cisplatin with definitive and adjuvant intent., Materials and Methods: Tapentadol PR was administered at the moment of pain onset in opioid-naive patients at the dosage of 50 mg BID. The dosage was increased 50 mg twice a day until the optimal dose of no more than 500 mg/day of tapentadol PR. Primary endpoint of the analysis was the evaluation of improved assessment using the numerical rating scale (NRS). Secondary endpoints were as follows: (1) assessment of the treatment received using the patients' global impression of change (PGIC) scale; (2) weight increase/stability; (3) sleep quality; and (4) tolerability. The period of observation was 90 days from the start of antineoplastic treatment., Results: Between September 2014 and May 2015, 30 HNC patients were observed. The average age was 64.9 years (range, 36-80). Twenty-two days after the start of antineoplastic treatment, tapentadol PR was administered to 25 % of patients. This percentage was increased to 50 % after 39 days and to 75 % after 43 days. Considering the efficacy of tapentadol PR on daily pain, there was a reduction of 30 % (95 % C.I. 69.3 ÷ 96.2 %) in the pain score in 26 patients (86.7 %), and a reduction of 50 % (95 % C.I. 57.7 ÷ 90.1 %) in 23 patients (76.7 %)., Conclusion: The use of tapentadol PR is feasible and well tolerated in HNC patients affected by background pain due to painful mucositis during intensity modulated radiotherapy with or without cisplatin. Further studies are needed to enhance current findings.

Background & Objectives: The main goal when treating malignancies with radiation is to deprive tumour cells of their reproductive potential. One approach is to induce tumour cell apoptosis. This study was conducted to evaluate the ability of carbon ions ( [12] C) to induce apoptosis and cell cycle arrest in human HTB140 melanoma cells., Methods: In this in vitro study, human melanoma HTB140 cells were irradiated with the 62 MeV/n carbon ( [12] C) ion beam, having two different linear energy transfer (LET) values: 197 and 382 keV/μm. The dose range was 2 to 16 Gy. Cell viability was estimated by the sulforhodamine B assay seven days after irradiation. The cell cycle and apoptosis were evaluated 48 h after irradiation using flow cytometry. At the same time point, protein and gene expression of apoptotic regulators were estimated using the Western blot and q-PCR methods, respectively., Results: Cell viability experiments indicated strong anti-tumour effects of [12] C ions. The analysis of cell cycle showed that [12] C ions blocked HTB140 cells in G2 phase and induced the dose dependent increase of apoptosis. The maximum value of 21.8 per cent was attained after irradiation with LET of 197 keV/μm at the dose level of 16 Gy. Pro-apoptotic effects of [12] C ions were confirmed by changes of key apoptotic molecules: the p53, Bax, Bcl-2, poly ADP ribose polymerase (PARP) as well as nuclear factor kappa B (NFκB). At the level of protein expression, the results indicated significant increases of p53, NFκB and Bax/Bcl-2 ratio and PARP cleavage. The Bax/Bcl-2 mRNA ratio was also increased, while no change was detected in the level of NFκB mRNA., Interpretation & Conclusions: The present results indicated that anti-tumour effects of [12] C ions in human melanoma HTB140 cells were accomplished through induction of the mitochondrial apoptotic pathway as well as G2 arrest., Competing Interests: None.

Diethylene glycol (DEG) is largely used during oil and gas exploitation by offshore platforms. The aim of this work was to investigate if this compound induces direct molecular/cellular effects in marine organisms, or indirectly modulate those of produced waters (PWs). Sea bass (Dicentrarchus labrax) were exposed to DEG dosed alone or in combination with PWs from an Adriatic platform. A wide array of analysed biomarkers included cytochrome P450-dependent enzymatic activity, bile metabolites, glutathione S-transferases, acetylcholinesterase, peroxisomal proliferation, antioxidant defences (catalase, glutathione reductase, glutathione peroxidases, glutathione), total oxyradical scavenging capacity, malondialdehyde and DNA integrity (single strand breaks and frequency of micronuclei). Results did not reveal marked effects of DEG, while PWs influenced the biotransformation system, the oxidative status and the onset of genotoxic damages. Co-exposures caused only limited differences of biomarker responses at some experimental conditions, overall suggesting a limited biological impact of DEG at levels normally deriving from offshore activities.

Unlabelled: Benign paroxysmal positional vertigo (BPPV) of lateral semicircular canal (LSC) is one of the rarer forms of BPPV as compared to posterior semicircular canal BPPV. Various particle repositioning manoeuvres have been described in the literature as a mode of treating this condition., Purpose: Evaluation and discussion of the procedure of the Gufoni's manoeuvre and its advantages in the treatment of BPPV of LSC., Material and Methods: Prospective study of 58 patients affected by LSC BPPV who were office-treated with Gufoni's manoeuvre., Results: Seventy-nine percent of the patients so treated had complete resolution of symptoms, and 6.9% did not show any improvement in their symptoms. The remaining 13.8% had a conversion into posterior semicircular canal BPPV during treatment and were successfully treated with Epley's or Semont's manoeuvre., Conclusions: Gufoni's manoeuvre is effective in treating patients suffering from BPPV of LSC; it is simple to perform; there are not many movements to execute, it needs low time of positioning, and positions are comfortable to the patient.

Here, we present the case of an extremely subtle peripheral graft infection caused by Staphylococcus aureus. The lack of local signs and the negativity of all imaging studies, including (99m)Tc-HMPAO-Labelled-Leukocyte Scan which is reported to have 100% sensitivity, delayed the diagnosis and therapy, which were both provided by surgery.

Objective: To evaluate the efficacy of subclavian stenosis percutaneous transfemoral angioplasty (PTA)-treatment in patients with intermittent or complete subclavian steal syndrome (SSS), and coronary-subclavian steal syndrome (C-SSS) after left internal mammary artery-interventricular anterior artery (LIMA-IVA) by pass graft., Methods: We studied 42 patients with coronary subclavian steal syndrome subdivided in two groups; the first group consisted of 15 patients who presented an intermittent vertebral-subclavian steal, while the second group consisted of 27 patients with a complete vertebral-subclavian steal. All patients were treated with angioplasty and stent application and were followed up for a period of 5 years by echocolordoppler examination to evaluate any subclavian restenosis., Results: Subclavian restenosis was significantly increased in patients with a complete subclavian steal syndrome. The restenosis rate was 6.67% in the first group and 40.75% in the second group, These patients had 9.1 fold-increase risk (CI confidence interval 0.95-86.48) in restenosis., Conclusion: Patients with a complete subclavian and coronary steal syndrome present a higher risk of subclavian restenosis.

2C-T-7 ('Blue Mystic'), an illicit compound which shows similarities with MDMA and other designer drugs, has been only occasionally identified in the EU, but discussion on the Internet between experimenters has recently grown significantly. We aimed at collecting together in a review the available information on 2C-T-7, both at the cyber and at the street market level. 2C-T-7 was first synthesized in 1986; its desired effects include both a sense of empathy and of well-being. Hallucinations, nausea, anxiety, panic attacks and paranoid ideation are anecdotally reported. According to the different European sources here approached, the availability of 2C-T-7 at street level seems to be currently very low, although one death related to a mono-intoxication with 2C-T-7 has been documented in the USA. With respect to information on 2C-T-7 available online, due to both redundancy and relevance issues the initial identified sample of 360 was reduced to 118 websites. In 14 (11.9%) websites, the detailed description of the 2C-T-7 synthesis was given. Harm Reduction websites appeared significantly earlier in the search engines results' list than Anti drugs (p 0.006) websites. Five (4.2%) websites apparently offered 2C-T-7 for sale. The large body of knowledge available online seems to contrast with small numbers of seizures at street level; an exhaustive web mapping of drug-related issues may be of interest for the clinician. Projects aimed at designing more 'attractive' prevention websites should be planned and future studies should better assess the characteristics of those consumers who take advantage of the online information of hallucinogenic compounds.

Matrix metalloproteinases (MMPs) have been implicated in the formation of microvessels during angiogenesis, but their role in vascular regression is poorly understood. The rat aorta model of angiogenesis was used to study the function of MMPs at different stages of the angiogenic process. Gelatin zymography and Western analysis demonstrated production of MMP-2 and MMP-9 by aortic outgrowths in serum-free collagen gel culture. MMP-2 was found in both culture medium and collagen gel, whereas MMP-9 was predominantly associated with the gel. MMP expression increased gradually during the angiogenic growth phase and stayed high when vessels regressed and collagen lysed around the aortic rings. The MMP inhibitors, batimastat and marimastat, blocked formation of microvessels when added to the culture medium at the beginning of the experiment. They, however, stabilized the microvessels and prevented vascular regression after the angiogenic growth phase. This effect was observed also under conditions of angiogenic stimulation by basic fibroblast growth factor. MMP inhibitor-mediated stabilization of microvessels was associated with inhibition of collagen lysis and accumulation of collagen fibrils in the subendothelial space. This study demonstrates that MMPs promote microvessel formation during the early stages of angiogenesis, but also contribute to the reabsorption of the neovasculature in the later stages of this process. The time-dependent divergent effects of MMPs on microvessel growth and survival may influence the in vivo activity of MMP inhibitors used to treat angiogenesis-dependent disorders.