Decreases in serum PFAS are associated with decreases in serum lipids: A longitudinal study on a highly exposed population.

INTRODUCTION: Perfluoroalkyl substances (PFAS) are widely used, ubiquitous and highly persistent man-made chemicals. Previous cross-sectional studies have consistently linked PFAS exposure to alterations in lipid profiles. However, longitudinal investigations are preferred to mitigate issues related to reverse causation and confounding. Hence, we aimed to investigate the association between changes in serum PFAS and changes in serum lipids, while shedding light on potential modifiers of the examined relationships. METHODS: We used data from a health surveillance program offered to residents of a vast area of the Veneto Region (North-Eastern Italy), who had been exposed to PFAS via contaminated drinking water until 2013. We included subjects aged ≥20 years who provided two blood samples over an average 4-year interval (n = 8101). We examined the relationships between changes in PFOA, PFOS and PFHxS and changes in total cholesterol (TC), high-density lipoprotein cholesterol (HDLC) and low-density lipoprotein cholesterol (LDL-C). Linear models were fitted for change in the natural logarithm (ln) of each lipid in relation to the change in the ln of PFAS. From the estimated regression coefficients, we calculated the predicted percentage change in the response for a ln-decrease in PFAS serum concentrations. RESULTS: Overall concentrations of PFOA, PFOS, PFHxS fell by 62.1 %, 24.4 % and 35.4 % from baseline, while small increases in lipids were observed. Declines in PFAS concentrations were associated with decreases in all lipids. For a ln-decrease in PFOA HDL-C decreased by 1.99 % (95 % CI: 1.28, 2.70), TC by 1.49 % (95 % CI: 0.88, 2.10), and LDL-C by 1.40 % (95 % CI: 0.45, 2.37). CONCLUSIONS: We found a positive association between changes in PFAS concentrations and changes in cholesterol levels, observing the most marked contrasts across sexes and age groups. Our findings support the reversibility of the associations identified in cross-sectional analyses, emphasizing the importance of water treatment measures in mitigating adverse health effects.

A generalized numerical model for clonal growth in scleractinian coral colonies.

Coral reefs, vital ecosystems supporting diverse marine life, are primarily shaped by the clonal expansion of coral colonies. Although the principles of coral clonal growth, involving polyp division for spatial extension, are well-understood, numerical modelling efforts are notably scarce in the literature. In this article, we present a parsimonious numerical model based on the cloning of polyps, using five key parameters to simulate a range of coral shapes. The model is agent-based, where each polyp represents an individual. The colony's surface expansion is dictated by the growth mode parameter (s), guiding the preferred growth direction. Varying s facilitates the emulation of diverse coral shapes, including massive, branching, cauliflower, columnar and tabular colonies. Additionally, we introduce a novel approach for self-regulatory branching, inspired by the intricate mesh-like canal system and internode regularity observed in Acropora species. Through a comprehensive sensitivity analysis, we demonstrate the robustness of our model, paving the way for future applications that incorporate environmental factors, such as light and water flow. Coral colonies are known for their high plasticity, and understanding how individual polyps interact with each other and their surroundings to create the reef structure has been a longstanding question in the field. This model offers a powerful framework for studying these interactions, enabling a future implementation of environmental factors and the possibility of identifying the key mechanisms influencing coral colonies' morphogenesis.

Preliminary analysis of the melanoma multimedia educational program for general practitioners on behalf of the Italian Melanoma Intergroup.

According to the National Oncological Plan 2023-2027 on the importance of multidisciplinary and interactive e-learning training, the Italian Melanoma Intergroup (IMI) has developed MelaMEd (Melanoma Multimedia Education), a national project for general practitioners (GPs) on the prevention and detection of cutaneous melanoma through an online platform and an online course. MelaMEd enables participants to i) recognize skin lesions that require specialist dermatological assessment, ii) select patients at high risk of melanoma and iii) be informed of the diagnosis and treatment pathway of patients with melanoma. A free online platform and online course were developed and launched in June 2022. Before starting the course, enrolled participants fill out a pre-training questionnaire concerning the basic knowledge of the disease and the recognition and management of suspicious lesions. After the course, participants will fill out the same questionnaire again. The online course will end in December 2023. Here we present a preliminary analysis of the pre-training results (January 2023-July 2023). The data have been analyzed descriptively. So far, five healthcare centers have participated in the project for a total of 1320 participants. Of these, 298 compiled the pre-training questionnaire. Forty-seven percent of them were aged <40 years. Respondents were almost divided between GPs (47%) and resident GPs (48%). Among the theoretical questions, the ABCDE rule and ugly duckling sign are well known (96% and 91% of correct answers, respectively), but a lower percentage (68%) of respondents knows the EFG rule for the recognition of nodular melanomas and the statement of Breslow thickness (29%). Regarding the series of clinical images of pigmented skin lesions and their management, the percentages rate of accuracy varied from 33% to 87%: melanoma (5 cases) ranges from 36% to 71%, melanocytic nevi (3 cases) from 33% to 84%, whereas the percentages rate of referral for dermatological evaluation varied from 44% to 99%. Melanoma cases referred to dermatologist ranges from 67% to 99%. This preliminary analysis on pre-train-ing questionnaire mainly showed a lack of knowledge of the two major points of melanoma diagnosis (EFG) and management (Breslow thickness), as well as a low rate of participants. We will compare the proportions of correct answers to the questionnaires before and after the course once available.

Comparison between clinical and cytological findings in chronic rhinosinusitis with nasal polyps treated with Dupilumab.

PURPOSE: Biologics represent a new therapeutic strategy for severe and recurrent chronic rhinosinusitis with nasal polyps (CRSwNP). Usually, their actual therapeutic effectiveness is assessed by reduction in nasal polyps and/or improvement in nasal symptoms and quality of life. However, these measures do not consider nasal immunophlogosis, which can be evaluated through nasal cytology. The purpose of this study was to assess not only the clinical impact but also the cellular changes in the nasal inflammatory infiltrate observed through nasal cytology of CRSwNP patients treated with Dupilumab for 24 months. METHODS: Fifty-five CRSwNP patients treated with Dupilumab were collected. Patients were evaluated before starting treatment and at one, three, six, nine months, one year, one and a half years, and two years after the first drug administration. During follow-up visits patients underwent endoscopic evaluation, nasal symptoms and quality of life assessment, complete blood count and nasal cytology. RESULTS: During follow-up, significant improvement was found in Nasal Polyps Score (NPS), nasal patency, olfaction, Sino-Nasal Outcome Test (SNOT-22) score, and Visual Analogue Scale (VAS). Regarding nasal cytology, a reduction in eosinophils and mast cells in the cellular infiltrate was observed over the two-year follow-up period compared to baseline. CONCLUSION: Dupilumab has demonstrated broad efficacy in the management of CRSwNP from both clinical and cytological findings. Further studies are needed to confirm our findings and evaluate the biologics' impact on nasal mucosal inflammatory cells by nasal cytology with the aim of better identifying each patient's endotype and predicting the response to biologics.

Anticancer Activity and Mechanism of Action of Couroupita guianensis Bark Decoction in Gastric Adenocarcinoma Cancer Cell Line.

Couroupita guianensis, a medicinal plant autochthonal to South America and South India, is widely used in the ethnomedicine of the indigenous peoples of these regions thanks to its alleged antimicrobial, anti-inflammatory, antioxidant and wound-healing properties. The majority of studies have mainly analyzed organic extracts of the Indian plant's flowers and leaves, with limited research on its bark decoction, traditionally used in Amazonian shamanic medicine. In this study, we investigated the anticancer effects of the bark decoction and its main fractions obtained through chromatographic separation, as well as the underlying molecular mechanisms in AGS gastric cancer cells. Viability, cell proliferation, cell cycle, apoptosis and protein expression related to these processes were evaluated. Both the bark decoction and fraction III significantly inhibited cell viability, and the cytotoxic effect was linked to cell cycle blockade and the induction of apoptosis also through an engulfment of the autophagic flux. Increased expression or activation of the key proteins (p53, p21, cdk2, Bak, caspases, pAMPK, pAkt, beclin, p62 and LC3BII) involved in these processes was observed. The results obtained confirmed an important anticancer effect of C. guianensis bark decoction, providing scientific validation for its use in traditional medicine and highlighting its potential as a therapeutic agent against gastric cancer.

A personalized clinical assessment: multi-sensor approach for understanding musculoskeletal health in the frail population.

BACKGROUND: Sarcopenia is a muscle disorder causing a progressive reduction of muscle mass and strength, but the mechanism of its manifestation is still partially unknown. The three main parameters to assess are: muscle strength, muscle volume or quality and low physical performance. There is not a definitive approach to assess the musculoskeletal condition of frail population and often the available tests to be performed in those clinical bedridden patients is reduced because of physical impairments. In this paper, we propose a novel instrumental multi-domain and non-invasive approach during a well-defined protocol of measurements for overcoming these limitations. A group of 28 bedridden elder people, subjected to surgery after hip fracture, was asked to perform voluntary isometric contractions at the 80% of their maximum voluntary contraction with the non-injured leg. The sensor employed before and/or during the exercise were: ultrasound to determine the muscle architecture (vastus lateralis); force acquisition with a load cell placed on the chair, giving an indication of the muscle strength; surface electromyography (EMG) for monitoring muscular electrical activity; time-domain (TD) near-infrared spectroscopy (NIRS) for evaluating muscle oxidative metabolism. RESULTS: A personalized "report card" for each subject was created. It includes: the force diagram (both instantaneous and cumulative, expected and measured); the EMG-force diagram for a comparison between EMG derived median frequency and measured force; two graphs related to the hemodynamic parameters for muscle oxidative metabolism evaluation, i.e., oxy-, deoxy-, total-hemoglobin and tissue oxygen saturation for the whole exercise period. A table with the absolute values of the previous hemodynamic parameters during the rest and the ultrasound related parameters are also included. CONCLUSIONS: In this work, we present the union of protocols, multi-domain sensors and parameters for the evaluation of the musculoskeletal condition. The novelties are the use of sensors of different nature, i.e., force, electrical and optical, together with a new way to visualize and combine the results, by means of a concise, exhaustive and personalized medical report card for each patient. This assessment, totally non-invasive, is focused on a bedridden population, but can be extended to the monitoring of rehabilitation progresses or of the training of athletes.

Investigating pollution input to coastal groundwater-dependent ecosystems in dry Mediterranean agricultural regions.

The insufficient taking into account of groundwater as a basis for implementing protection measures for coastal wetlands can be related to the damage they are increasingly exposed to. The aim of this study is to demonstrate the pertinence of combining hydrogeological tools with assessment of pollutant fluxes and stable isotopes of O, H and N, as well as groundwater time-tracers to identify past and present pollution sources resulting from human activities and threatening shallow groundwater-dependent ecosystems. A survey combining physico-chemical parameters, major ions, environmental isotopes (18O, 2H, 15N and 3H), with emerging organic contaminants including pesticides and trace elements, associated with a land use analysis, was carried out in southern Italy, including groundwater, surface water and lagoon water samples. Results show pollution of the shallow groundwater and the connected lagoon from both agricultural and domestic sources. The N-isotopes highlight nitrate sources as coming from the soil and associated with the use of manure-type fertilizers related to the historical agricultural context of the area involving high-productivity olive groves. Analysis of EOCs has revealed the presence of 8 pesticides, half of which have been banned for two decades and two considered as pollutant legacies (atrazine and simazine), as well as 15 molecules, including pharmaceuticals and stimulants, identified in areas with human regular presence, including rapidly degradable compounds (caffeine and ibuprofen). Results show that agricultural pollution in the area is associated with the legacy of intensive olive growing in the past, highlighting the storage capacity of the aquifer, while domestic pollution is sporadic and associated with regular human presence without efficient modern sanitation systems. Moreover, results demonstrate the urgent need to consider groundwater as a vector of pollution to coastal ecosystems and the impact of pollutant legacies in planning management measures and policies, with the aim of achieving 'good ecological status' for waterbodies.

Human immunodeficiency virus-associated Lymphomas: EHA-ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up.

This EHA-ESMO Clinical Practice Guideline provides key recommendations for managing HIV-associated lymphomas.The guideline covers clinical, imaging and pathological diagnosis; staging and risk assessment; treatment and follow-up.The author group encompasses a multidisciplinary group of experts from different institutions and countries in Europe.Recommendations are based on available scientific data and the authors' collective expert opinion.

First Results of NURE-Combo: A Phase II Study of Neoadjuvant Nivolumab and Nab-Paclitaxel, Followed by Postsurgical Adjuvant Nivolumab, for Muscle-Invasive Bladder Cancer.

PURPOSE: To evaluate the activity and safety of nivolumab with nab-paclitaxel as neoadjuvant therapy, followed by radical cystectomy (RC) and postsurgical adjuvant nivolumab in patients with muscle-invasive bladder cancer (MIBC). PATIENTS AND METHODS: Eligible patients had an Eastern Cooperative Oncology Group performance status of ≤1 and a T2-4aN0-1M0 stage with >50% urothelial carcinoma histology and were ineligible for or refused cisplatin-based chemotherapy. Patients received four cycles of nivolumab 360 mg once every 3 weeks + nab-paclitaxel 125 mg/m2 once on days 1 and 8, every 3 weeks, followed by RC, and then adjuvant nivolumab 360 mg once every 3 weeks × 13 cycles. The primary end point was the pathologic complete response (CR) rate (ypT0N0). Secondary end points were major pathologic response (ypT≤1N0), safety, event-free survival (EFS), and overall survival. RESULTS: Thirty-one patients were enrolled from December 2021 to June 2023; 19 (61.3%) had a cT2 stage, two (6.5%) had N1 stage, and 16 (51.6%) had a variant histology. Five patients (16.1%) received less than four full courses of neoadjuvant treatment because of treatment-related adverse events (TRAEs). Grade 3/4 TRAEs occurred in eight patients (25.8%). Twenty-eight patients underwent RC, and three refused RC after evidence of clinical CR and received a redo transurethral resection of the bladder tumor (reTURBT). The trial met its primary end point: 10 patients (32.3%; 95% CI, 16.7 to 51.4) achieved an ypT0N0 response. By including those who underwent reTURBT, 22 (70.9%; 95% CI, 55 to 87) achieved an ypT≤1N0-x response. After a median follow-up of 12 months (range, 5-22), two patients had a disease relapse after surgery. The 12-month EFS was 89.8% (95% CI, 79.5 to 100). CONCLUSION: To our knowledge, the first results from NURE-Combo trial suggest that this combination could expand the therapeutic opportunities of immune-chemotherapy in patients with MIBC.

Post-Kidney Transplant Cancer: A Real-World Retrospective Analysis From a Single Italian Center.

We describe the epidemiology of cancer after kidney transplantation (KTx), investigating its risk factors and impact on therapeutic management and survival in KTx recipients (KTRs). The association between modification of immunosuppressive (IS) therapy after cancer and survival outcomes was analyzed. We collected data from 930 KTRs followed for 7 [1-19] years. The majority of KTRs received KTx from a deceased donor (84%). In total, 74% of patients received induction therapy with basiliximab and 26% with ATG. Maintenance therapy included steroids, calcineurin inhibitors, and mycophenolate. Patients with at least one cancer (CA+) amounted to 19%. NMSC was the most common tumor (55%). CA+ were older and had a higher BMI. Vasculitis and ADPKD were more prevalent in CA+. ATG was independently associated with CA+ and was related to earlier cancer development in survival and competing risk analyses (p = 0.01 and <0.0001; basiliximab 89 ± 4 vs. ATG 40 ± 4 months). After cancer diagnosis, a significant prognostic impact was derived from the shift to mTOR inhibitors compared to a definitive IS drug suspension (p = 0.004). Our data confirm the relevance of cancer as a complication in KTRs with ATG as an independent risk factor. An individualized choice of IS to be proposed at the time of KTx is crucial in the prevention of neoplastic risk. Finally, switching to mTORi could represent an important strategy to improve patient survival.

Targeting specific brain districts for advanced nanotherapies: A review from the perspective of precision nanomedicine.

Numerous studies are focused on nanoparticle penetration into the brain functionalizing them with ligands useful to cross the blood-brain barrier. However, cell targeting is also crucial, given that cerebral pathologies frequently affect specific brain cells or areas. Functionalize nanoparticles with the most appropriate targeting elements, tailor their physical parameters, and consider the brain's complex anatomy are essential aspects for precise therapy and diagnosis. In this review, we addressed the state of the art on targeted nanoparticles for drug delivery in diseased brain regions, outlining progress, limitations, and ongoing challenges. We also provide a summary and overview of general design principles that can be applied to nanotherapies, considering the areas and cell types affected by the most common brain disorders. We then emphasize lingering uncertainties that hinder the translational possibilities of nanotherapies for clinical use. Finally, we offer suggestions for continuing preclinical investigations to enhance the overall effectiveness of precision nanomedicine in addressing neurological conditions. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Neurological Disease Therapeutic Approaches and Drug Discovery > Emerging Technologies.

Iodinated gadolinium-gold nanomaterial as a multimodal contrast agent for cartilage tissue imaging.

Cartilage damage, a common cause of osteoarthritis, requires medical imaging for accurate diagnosis of pathological changes. However, current instruments can acquire limited imaging information due to sensitivity and resolution issues. Therefore, multimodal imaging is considered an alternative strategy to provide valuable images and analyzes from different perspectives. Among all biomaterials, gold nanomaterials not only exhibit outstanding benefits as drug carriers, in vitro diagnostics, and radiosensitizers, but are also widely used as contrast agents, particularly for tumors. However, their potential for imaging cartilage damage is rarely discussed. In this study, we developed a versatile iodinated gadolinium-gold nanomaterial, AuNC@BSA-Gd-I, and its radiolabeled derivative, AuNC@BSA-Gd-131I, for cartilage detection. With its small size, negative charge, and multimodal capacities, the probe can penetrate damaged cartilage and be detected or visualized by computed tomography, MRI, IVIS, and gamma counter. Additionally, the multimodal imaging potential of AuNC@BSA-Gd-I was compared to current multifunctional gold nanomaterials containing similar components, including anionic AuNC@BSA, AuNC@BSA-I, and AuNC@BSA-Gd as well as cationic AuNC@CBSA. Due to their high atomic numbers and fluorescent emission, AuNC@BSA nanomaterials could provide fundamental multifunctionality for imaging. By further modifying AuNC@BSA with additional imaging materials, their application could be extended to various types of medical imaging instruments. Nonetheless, our findings showed that each of the current nanomaterials exhibited excellent abilities for imaging cartilage with their predominant imaging modalities, but their versatility was not comparable to that of AuNC@BSA-Gd-I. Thus, AuNC@BSA-Gd-I could be served as a valuable tool in multimodal imaging strategies for cartilage assessment.

PRONTO-TK: a user-friendly PROtein Neural neTwOrk tool-kit for accessible protein function prediction.

Associating one or more Gene Ontology (GO) terms to a protein means making a statement about a particular functional characteristic of the protein. This association provides scientists with a snapshot of the biological context of the protein activity. This paper introduces PRONTO-TK, a Python-based software toolkit designed to democratize access to Neural-Network based complex protein function prediction workflows. PRONTO-TK is a user-friendly graphical interface (GUI) for empowering researchers, even those with minimal programming experience, to leverage state-of-the-art Deep Learning architectures for protein function annotation using GO terms. We demonstrate PRONTO-TK's effectiveness on a running example, by showing how its intuitive configuration allows it to easily generate complex analyses while avoiding the complexities of building such a pipeline from scratch.

Omission of Radiotherapy in Primary Mediastinal B-Cell Lymphoma: IELSG37 Trial Results.

BACKGROUND: The role of consolidation radiotherapy in primary mediastinal B-cell lymphoma (PMBCL) patients is controversial. METHODS: The IELSG37 trial, a randomized non-inferiority study, aimed to assess whether irradiation can be omitted in PMBCL patients with complete metabolic response (CMR) after induction immunochemotherapy. Primary endpoint was progression-free survival (PFS) at 30 months post-randomization. Patients with CMR were randomly assigned to observation or consolidation radiotherapy (30 Gy). With a non-inferiority margin of 10% (assuming a 30-month PFS of 85% in both arms), a sample size of 540 patients was planned with 376 expected to be randomized. RESULTS: The observed events were considerably lower than expected, therefore, primary endpoint analysis was conducted when ≥95% of patients were followed for ≥30 months. Of 545 patients enrolled, 268 were in CMR after induction and were randomized to observation (n=132) or radiotherapy (n=136). The 30-month PFS was 96.2% in the observation arm and 98.5% in the radiotherapy arm, with a stratified hazard ratio of 1.47 (95%CI, 0.34 to 6.28) and absolute risk difference of 0.68% (95%CI, -0.97% to 7.46%). The 5-year overall survival was 99% in both arms.Non-randomized patients were managed according to local policies. Radiotherapy was the only treatment in 86% of those with Deauville score (DS) 4 and in 57% of those with DS 5. The 5-year PFS and OS of patients with DS 4 (95.8% and 97.5%, respectively) were not significantly different from those of randomized patients. Patients with DS5 had significantly poorer 5-year PFS and OS (60.3% and 74.6%, respectively). CONCLUSIONS: This study, the largest randomized trial of radiotherapy in PMBCL, demonstrated favorable outcomes in patients achieving CMR with no survival impairment for those omitting irradiation.

Arterial hypoperfusion as a negative predictive marker for primary hepatic malignancies treated with Y-90 glass microsphere transarterial radioembolization.

Background: Radioembolization with yttrium-90 (Y-90) is utilized to treat primary liver malignancies. The efficacy of this intra-arterial therapy in arterially hypoperfused tumors is not known. Methods: We reviewed data of patients with primary liver tumors treated with Y-90 prescription doses of at least 150 Gy. Baseline patient characteristics, treatment history, imaging-based tumor response assessments, and clinical outcome metrics were recorded. Tumors were classified as arterially hyperperfused versus hypoperfused on post-TARE Y-90 SPECT/CTs or pre-TARE hepatic perfusion SPECT/CTs. Perfusion status was correlated with tumor response assessments and clinical outcomes. Cox proportional hazards models were utilized to compare survival and progression-free survival. Inverse probability weighting was utilized to account for clinical factors and adjusted multivariable proportional hazards analyses to examine the relationship of quantitative perfusion and cancer outcomes. Results: Of 400 Y-90 treatments, 88 patients received a prescribed dose of at least 150 Gy and had pre- or post-treatment SPECT/CT images. 11 and 77 patients had arterially hypoperfused and hyperperfused lesions, respectively. On dedicated liver MRI or CT at 3 months after Y-90, the complete response rates were 5.6% and 16.5% in the hypoperfused and hyperperfused cohort, respectively (P = 0.60). When controlling for various clinical features, including tumor histology, patients with arterially hypoperfused tumors had significantly shorter progression-free survival (HR 1.87, 95% CI - 1.03 - 3.37, P = 0.039) and greater elsewhere liver (HR 3.36, 95% CI = 1.23 - 9.20, P = 0.019) and distant failure (HR 7.64 (2.71 - 21.54, P < 0.001). In inverse probability weighted analysis, patients with arterially hypoperfused tumors had worse overall survival (P = 0.032). In the quantitative analysis, lower levels of lesion perfusion were also associated with worse clinical outcomes, again controlling for tumor histology. Conclusion: Compared to arterially hyperperfused tumors, hypoperfused primary liver tumors treated with Y-90 may have worse clinical outcomes.