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Abstract Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic and lethal disease. Gasdermins are primarily associated with necrosis via membrane permeabilization and pyroptosis, a lytic pro‐inflammatory type of cell death. In this study, GSDMC upregulation during PDAC progression is reported. GSDMC directly induces genes related to stemness, EMT, and immune evasion. Targeting Gsdmc in murine PDAC models reprograms the immunosuppressive tumor microenvironment, rescuing the recruitment of anti‐tumor immune cells through CXCL9. This not only results in diminished tumor initiation, growth and metastasis, but also enhances the response to KRASG12D inhibition and PD‐1 checkpoint blockade, respectively. Mechanistically, it is discovered that ADAM17 cleaves GSDMC, releasing nuclear fragments binding to promoter regions of stemness, metastasis, and immune evasion‐related genes. Pharmacological inhibition of GSDMC cleavage or prevention of its nuclear translocation is equally effective in suppressing GSDMC's downstream targets and inhibiting PDAC progression. The findings establish GSDMC as a potential therapeutic target for enhancing treatment response in this deadly disease.

Summary: Background: We studied the poorly-known dynamics of circulating DNA (cir-nDNA), as monitored prospectively over an extended post-surgery period, in patients with cancer. Methods: On patients with stage III colon cancer (N = 120), using personalised molecular tags we carried out the prospective, multicenter, blinded cohort study of the post-surgery serial analysis of cir-nDNA concentration. 74 patients were included and 357 plasma samples tested. Findings: During post-operative follow-up, the patients’ median cir-nDNA concentration was greater (P 18 months post-surgery, the data suggest that the persistence of NETs formation is not due to the adjuvant CT. Interpretation: (1), Given the inter-patient heterogeneity, the post-surgery cir-nDNA level cannot be considered a reliable value, and caution must be exercised when determining mutation allele frequency or the mutation status; and (2), specific studies must be undertaken to investigate the possible clinical impact of the persistent, low-grade inflammation resulting from elevated NETs levels, such as observed in these post-surgery patients, given that such levels are known to potentially induce adverse cardiovascular or thrombotic events. Funding: This work was supported by the H2020 European ERA-NET grant on Translational Cancer Research (TRANSCAN-2).

Summary: Pancreatic ductal adenocarcinoma (PDAC) poses significant clinical challenges, often presenting as unresectable with limited biopsy options. Here, we show that circulating tumor cells (CTCs) offer a promising alternative, serving as a “liquid biopsy” that enables the generation of in vitro 3D models and highly aggressive in vivo models for functional and molecular studies in advanced PDAC. Within the retrieved CTC pool (median 65 CTCs/5 mL), we identify a subset (median content 8.9%) of CXCR4+ CTCs displaying heightened stemness and metabolic traits, reminiscent of circulating cancer stem cells. Through comprehensive analysis, we elucidate the importance of CTC-derived models for identifying potential targets and guiding treatment strategies. Screening of stemness-targeting compounds identified stearoyl-coenzyme A desaturase (SCD1) as a promising target for advanced PDAC. These results underscore the pivotal role of CTC-derived models in uncovering therapeutic avenues and ultimately advancing personalized care in PDAC.

Background:. Microsurgery has a steep learning curve. Synthetic simulators have proven to be useful training tools for the initial learning stages, as well as being ethically sound, viable, safe, and cost-effective. The objective of this review was to determine the quality, effectiveness, and validity of these simulators as well as to assess their ability to evaluate microsurgical skills. Methods:. A systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines was performed. We searched databases (Web of Science, Scopus, and PubMed) to identify original articles describing synthetic training models for microsurgery. Three reviewers evaluated articles for inclusion following predefined selection criteria. Data were extracted from full-texts of included articles. Results:. Thirty-nine studies met the inclusion criteria. A total of 38 different devices have been recorded. Microsurgical training devices offer a low-cost, fast, and consistent method to concretely quantify and assess the initial microsurgical skills of trainees using standardized exercises that can be scored by the examiner. According to the authors, the outcomes were satisfactory, with a tangible improvement in microsurgical abilities, despite the lack of a common comparison scale. Conclusions:. Thanks to their availability, cost, and effectiveness, synthetic models are the recommended option to train basic, intermediate and advanced procedures before executing them on in vivo models.

Resveratrol (RV), a natural polyphenol found in various plants, exhibits a wide range of bioactive properties and mechanisms of action. Its potential therapeutic benefits in several diseases and, more specifically, in ocular diseases have garnered significant attention, with studies exploring RV properties at cellular, molecular, and physiological levels. Like many natural derivatives, RV can be obtained through various extraction methods from plant sources, with a growing interest in sustainable techniques that align with recent trends in sustainability, circular economy, and green chemistry. This review begins by describing the most efficient and sustainable extraction techniques of RV from natural sources and then delves into its numerous bioactive properties and its synergistic effects with other active substances and drugs. Furthermore, an overview of the scientific literature on RV as a therapeutic agent for ocular diseases, both in its pure form and entrapped in nanoparticulate systems, is provided.

Background Soft tissue reconstruction around the knee area is still an open question, particularly in persistent infections and multiple reoperations scenario. Flap coverage should guarantee joint mobility and protection, even when foreign materials are implanted. The chimeric harvesting of the musculocutaneous gastrocnemius flap, based on the sural artery perforators, can extend its applicability in soft tissue reconstruction of the upper leg, overcoming the drawbacks of the alternative pedicled flaps.

The integration of remote sensing and socio-economic data is crucial for policy making in regions suffering from water scarcity and climate change. We present a framework that combines remotely sensed estimates of biomass and water use from FAO’s Water Productivity Open-access portal (WaPOR) (V2) with an ensemble of calibrated mathematical programming models to assess the impact of water reallocations on rain-fed and irrigated land use and production in water-stressed basins. We evaluated our model in the Upper Litani Basin of Lebanon using two water reallocation policies: (i) quotas that progressively reduces water allocation for irrigation up to 100%, at 1% intervals and (ii) a pricing policy that increases the agricultural water price up to 0.25 USD/m3, at 0.0025 USD/m3 intervals. Our results reveal that 1) the impacts of water availability reductions due to quotas on profit and employment are less-than-proportional when water allocation is reduced by 50%; 2) irrigators responses to prices are inelastic until a price increase of 0.03 USD/m3, become significantly more elastic afterwards, and again become inelastic above a price increase of 0.06 USD/m3; 3) higher water prices progressively reduce profit and labor, significantly reduce water use over the elastic interval (where irrigators cultivating low value-added crops shift to rainfed agriculture), and increase tariff revenue during the inelastic interval (where irrigators largely stick to their crop portfolios and pay the higher water prices). Our results reveal nontrivial uncertainties and tipping points, thus highlighting the value of combining reliable water use data with multi-model and multi-scenario ensembles in informing robust policies.

This review aims to provide a comprehensive overview of various aspects related to cosmetic product packaging, highlighting both advancements and challenges in the field. Initially, it offers a general description of the main materials used in cosmetic containers, including plastic, glass, paper, and aluminum. This is followed by an analysis of the existing EU legislative frameworks that govern cosmetic packaging, encompassing chemical, food, and waste regulations. The paper also discusses recent EU regulatory proposals and guidelines from trade associations aimed at enhancing the sustainability of cosmetic packaging materials. Additionally, the role of recycled and bio-based packaging materials in promoting environmental sustainability is analyzed. Overall, this review aims to provide insights for experts in the field on how to balance safety, functionality, and environmental responsibility in cosmetic packaging.

Open partial horizontal laryngectomies (OPHLs) represent a valuable therapeutic option for tumors of the intermediate T-category and, in selected cases, for locally advanced tumors with low-volume extra-laryngeal extension. The eligibility of patients treated with this type of surgery has increased with the introduction of the modular approach to OPHL planning. This strategy follows the introduction of the classification proposed by the European Laryngological Society, based on the extent of horizontal resection. Optimization of the selection is the result of a meticulous work-up process involving close cooperation between experienced surgeons and radiologists, followed by final quality control by pathologists. Computed tomography and magnetic resonance imaging are study methods whose pearls and pitfalls are well known, especially when performed at a high level of expertise. In this paper, based on the experience of two high-volume centers, a checklist of 20 questions addressed by the surgeon to the radiologist before planning an OPHL was proposed. Considerations regarding case selection are reported for each of the questioned parameters. A very simple question-and-answer process is easy to understand and mainly addressed by less experienced colleagues who wish to increase their knowledge and skills in performing this type of surgery.

Fundamento: en este trabajo se analiza el impacto de la COVID-19 en el consumo de antidepresivos durante el primer año de la pandemia (2020) tomando como línea de base las tendencias de prescripción durante los 4 años anteriores (2016-2019) en la provincia de Santa Cruz de Tenerife y las cuatro islas que la conforman. Métodos: los datos de ventas en las farmacias comunitarias se tomaron como base de datos agregados. La dosis por 1000 habitantes y día se utilizó como indicador de consumo. Resultados: en las islas de El Hierro y La Gomera, el aumento de población no justifica por sí solo los incrementos relevantes observados en el consumo de antidepresivos y, posiblemente, la COVID-19 y sus consecuencias sobre la salud de la población podrían ser responsables de dichos aumentos. En la isla de Tenerife el incremento de población podría justificar, en gran medida, el ligero aumento de consumo observado. La isla de La Palma presenta un aumento de tan solo un 1,40 %, pero menor al valor esperado tomando como línea de base el periodo 2016-2019. Todas las islas presentan las mismas tendencias en el consumo de los diferentes subgrupos de antidepresivos y principios activos, aunque con ligeras variaciones, con la excepción de la isla de la Palma que presenta un comportamiento y tendencias estadísticamente diferentes. Conclusiones: las diferencias de prescripción observadas podrían estar relacionadas con las características sociosanitarias y demográficas de cada una de las islas.

Archive tissues are the most available source of human tissues useful for molecular analysis in translational research. The main issues for those specimens are the modification and degradation of biomolecules, namely proteins, DNA, and RNA. In the last decade, several high-throughput analytical methods have been applied to archive tissues. Although histological tissues are fixed in neutral-buffered formalin nowadays, in the recent past, Bouin’s solution was also used in tissue processing. The present study aims to investigate the feasibility of nCounter Nanostring hybridization in quantifying mRNA in highly degraded samples, such as Bouin’s fixed and paraffin-embedded (BFPE) tissues, in comparison to the standard formalin-fixed and paraffin-embedded (FFPE) tissues as a source of RNA. A total of 16 paraffin-embedded tissue blocks from eight patients were analyzed (8 were FFPE and 8 were BEPE). Nanostring technology was applied to 300 ng of each RNA sample, whereas 360 ng of the same templates were retrotranscribed and submitted to qPCR and ddPCR. Our results show that the Nanostring technology outperforms the reference methods (ddPCR and qPCR) in detecting target mRNA in FFPE and BFPE samples. However, even Nanostring technology does not escape the limitation imposed by the degradation of the RNA templates, which could lead to misleading conclusions on the gene expression level.

Abstract Background The “HER2-low” nomenclature identifies breast carcinomas (BCs) displaying a HER2 score of 1+/2+ in immunohistochemistry and lacking ERBB2 amplification. Whether HER2-low BCs (HLBCs) constitute a distinct entity is debated. Methods We performed DNA and RNA high-throughput analysis on 99 HLBC samples (n = 34 cases with HER2 score 1+/HLBC-1, n = 15 cases with HER2 score 2+ and ERBB2 not amplified/HLBC-2N, and n = 50 cases with score 2+ and ERBB2 copy number in the equivocal range/HLBC-2E). We compared the mutation rates with data from 1317 samples in the Memorial Sloan-Kettering Cancer Center (MSKCC) BC cohort and gene expression data with those from an internal cohort of HER2-negative and HER2-positive BCs. Results The most represented mutations affected PIK3CA (31/99, 31%), GATA3 (18/99, 18%), TP53 (17/99, 17%), and ERBB2 (8/99, 8%, private to HLBC-2E). Tumor mutational burden was significantly higher in HLBC-1 compared to HLBC-2E/N (P = 0.04). Comparison of mutation spectra revealed that HLBCs were different from both HER2-negative and HER2-positive BCs, with HLBC-1 resembling more HER2-negative tumors and HLBC-2 mutationally related to HER2-addicted tumors. Potentially actionable alterations (annotated by using OncoKB/ESCAT classes) affected 52 patients. Intra-group gene expression revealed overlapping features between HLBC-1 and control HER2-negative BCs, whereas the HLBC-2E tumors showed the highest diversity overall. The RNA-based class discovery analysis unveiled four subsets of tumors with (i) lymphocyte activation, (ii) unique enrichment in HER2-related features, (iii) stromal remodeling alterations, and (iv) actionability of PIK3CA mutations (LAURA classification). Conclusions HLBCs harbor distinct genomic features when compared with HER2-positive and HER2-negative BCs; however, differences across IHC classes were also unveiled thus dissecting the full picture of heterogeneity across HER2-low disease. The HLBC-2E category harbors most distinctive features, whereas HLBC-1 seems superimposable to HER2-negative disease. Further studies are needed to ascertain whether the four genomic-driver classes of the LAURA classification hold prognostic and/or predictive implications.

When the scrotal sac is entirely debrided following a Fournier gangrene, testes exposure poses unique challenges for the reconstructive surgeon. Despite the anterolateral thigh (ALT) flap is considered a workhorse in such context, aesthetic results are often suboptimal because of the lack of natural ptosis and patchwork appearance. We describe the use of a super-thin pedicled ALT flap for total scrotal reconstruction, modified according to a peculiar flap design and inset technique. A 42-year-old man was referred to our department for delayed total scrotal reconstruction 8 months after a Fournier gangrene extensive debridement. A super-thin pedicled ALT flap from the right thigh was designed: in the central portion of the ALT, a lateral skin paddle extension was marked to guarantee adequate posterior anchorage during insetting and ptosis of the scrotal sac. This particular flap arrangement has inspired the name “sombrero” as the shape is akin to the famous hat. No secondary refinements were needed, and the patient showed satisfying aesthetic and functional results at 12 months' follow-up. The ALT flap design “sombrero” modification proposed in this article can improve scrotum cosmesis and patient satisfaction in a single-stage single-flap procedure.

Total reconstruction of the penis (TPR) represents a challenge for urologists and plastic surgeons, especially when urethral length is severely reduced. We here describe, for the first time in an oncologic scenario, a double flap phalloplasty using a pedicled anterolateral thigh (ALT) flap for penile reconstruction and a radial forearm free flap (RFFF) for complete neourethra and glans reconstruction following penile amputation. A 48-year-old patient came to our department following a total penectomy with inferior urethral derivation. The indication for a double flap phalloplasty was posed as only way to fully reconstruct the urethra on its length avoiding possible complications of single flap reconstruction using tube-into-tube technique. Both flaps healed uneventfully with no neourethral strictures or fistulas described. At 18 months follow-up, the patient was extremely satisfied with the aesthetic result and was able to void in standing position. We think that a double free tissue transfer for TPR should be considered, particularly when a urethral length > 14 cm needs to be reconstructed. While the pedicled ALT can be used to reconstruct a proper penile shaft with an easily concealed scar, the RFFF can provide adequate neourethra length with satisfactory sensory recovery at the neoglans.