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ABSTRACT Background Morphological and vascular characteristics of breast cancer can change during neoadjuvant chemotherapy (NAC). Dynamic contrast‐enhanced magnetic resonance imaging (DCE‐MRI)‐acquired pre‐ and mid‐treatment quantitatively capture information about tumor heterogeneity as potential earlier indicators of pathological complete response (pCR) to NAC in breast cancer. Aims This study aimed to develop an ensemble deep learning‐based model, exploiting a Vision Transformer (ViT) architecture, which merges features automatically extracted from five segmented slices of both pre‐ and mid‐treatment exams containing the maximum tumor area, to predict and monitor pCR to NAC. Materials and Methods Imaging data analyzed in this study referred to a cohort of 86 breast cancer patients, randomly split into training and test sets at a ratio of 8:2, who underwent NAC and for which information regarding the pCR status was available (37.2% of patients achieved pCR). We further validated our model using a subset of 20 patients selected from the publicly available I‐SPY2 trial dataset (independent test). Results The performances of the proposed model were assessed using standard evaluation metrics, and promising results were achieved: area under the curve (AUC) value of 91.4%, accuracy value of 82.4%, a specificity value of 80.0%, a sensitivity value of 85.7%, precision value of 75.0%, F‐score value of 80.0%, and G‐mean value of 82.8%. The results obtained from the independent test show an AUC of 81.3%, an accuracy of 80.0%, a specificity value of 76.9%, a sensitivity of 85.0%, a precision of 66.7%, an F‐score of 75.0%, and a G‐mean of 81.2%. Discussion As far as we know, our research is the first proposal using ViTs on DCE‐MRI exams to monitor pCR over time during NAC. Conclusion Finally, the changes in DCE‐MRI at pre‐ and mid‐treatment could affect the accuracy of pCR prediction to NAC.

Coronary obstruction (CO) is a rare but potentially fatal complication of transcatheter aortic valve implantation (TAVI). The present article aims to summarize the evidence on CO risk factors and provide an overview of preventive strategies. We performed a comprehensive literature review focused on these items. The analysis included studies addressing patient-specific characteristics, procedural aspects, and the effectiveness of various prevention techniques in mitigating CO risk. Specific risk factors for CO, which can be assessed by evaluating patient characteristics using computed tomography, are described. Procedural factors associated with an increased risk of CO are discussed. Preventive techniques, including the chimney stent and bioprosthetic aortic scallop intentional laceration to prevent iatrogenic coronary artery obstruction (BASILICA), are also described, highlighting the advantages and disadvantages of each method. The present review also provides an overview of emerging dedicated devices designed to address this complication. In conclusion, identifying patients at risk for CO is crucial for optimizing TAVI outcomes. Comprehensive imaging assessment and appropriate preventive strategies, such as the BASILICA technique, can mitigate the risk of CO and improve patient outcomes. Further research is needed to validate emerging dedicated devices.

La obstrucción de las arterias coronarias (OC) es una complicación rara, pero potencialmente fatal, del implante percutáneo de válvula aórtica (TAVI). El objetivo de esta revisión es resumir la evidencia sobre los factores de riesgo de OC y las estrategias preventivas. Se realizó una revisión integral de la literatura centrada en estos aspectos. El análisis consideró estudios que abordaran las características del paciente, los factores procedimentales y la efectividad de diferentes técnicas preventivas para reducir el riesgo de OC. Se describen los factores relacionados con el paciente y del procedimiento que condicionan un mayor riesgo de OC. A lo largo del texto se detallan las técnicas para disminuir el riesgo de OC, incluidos el stent en chimenea y la técnica BASILICA. Además, se aporta una descripción general de los dispositivos diseñados para abordar esta complicación. En conclusión, la identificación de los factores de riesgo de OC es crucial para optimizar los resultados del TAVI. La evaluación exhaustiva mediante imagen multimodal, junto a estrategias preventivas apropiadas, como la técnica BASILICA, pueden mitigar el riesgo de OC y mejorar los resultados. Aún se requiere más investigación para validar los dispositivos emergentes.

ABSTRACT Limiting the availability of transition metals at infection sites serves as a critical defense mechanism employed by the innate immune system to combat microbial infections. Pseudomonas aeruginosa exhibits a remarkable ability to thrive in zinc-deficient environments, facilitated by intricate cellular responses governed by numerous genes regulated by the zinc-responsive transcription factor Zur. Many of these genes have unknown functions, including those within the predicted PA2911-PA2914 and PA4063-PA4066 operons. A structural bioinformatics investigation revealed that PA2911-PA2914 comprises a TonB-dependent outer membrane receptor and inner membrane ABC-permeases responsible for importing metal-chelating molecules, whereas PA4063-PA4066 contains genes encoding a MacB transporter, likely involved in the export of large molecules. Molecular genetics and biochemical experiments, feeding assays, and intracellular metal content measurements support the hypothesis that PA2911-PA2914 and PA4063-PA4066 are engaged in the import and export of the pyochelin-cobalt complex, respectively. Notably, cobalt can reduce zinc demand and promote the growth of P. aeruginosa strains unable to import zinc, highlighting pyochelin-mediated cobalt import as a novel bacterial strategy to counteract zinc deficiency. These results unveil an unexpected role for pyochelin in zinc homeostasis and challenge the traditional view of this metallophore exclusively as an iron transporter.IMPORTANCEThe mechanisms underlying the remarkable ability of Pseudomonas aeruginosa to resist the zinc sequestration mechanisms implemented by the vertebrate innate immune system to control bacterial infections are still far from being fully understood. This study reveals that the Zur-regulated gene clusters PA2911-2914 and PA4063-PA4066 encode systems for the import and export of cobalt-bound pyochelin, respectively. This proves to be a useful strategy to counteract conditions of severe zinc deficiency since cobalt can replace zinc in many proteins. The discovery that pyochelin may contribute to cellular responses to zinc deficiency leads to a reevaluation of the paradigm that pyochelin is a siderophore involved exclusively in iron acquisition and suggests that this molecule has a broader role in modulating the homeostasis of multiple metals.

Objective: Interleukin (IL)-22 is a potential therapeutic protein for the treatment of metabolic diseases such as obesity, type 2 diabetes, and metabolic dysfunction-associated steatotic liver disease due to its involvement in multiple cellular pathways and observed hepatoprotective effects. The short serum half-life of IL-22 has previously limited its use in clinical applications; however, the development of mRNA-lipid nanoparticle (LNP) technology offers a novel therapeutic approach that uses a host-generated IL-22 fusion protein. In the present study, the effects of administration of an mRNA-LNP encoding IL-22 on metabolic disease parameters was investigated in various mouse models. Methods: C57BL/6NCrl mice were used to confirm mouse serum albumin (MSA)-IL-22 protein expression prior to assessments in C57BL/6NTac and CETP/ApoB transgenic mouse models of metabolic disease. Mice were fed either regular chow or a modified amylin liver nonalcoholic steatohepatitis–inducing diet prior to receiving either LNP-encapsulated MSA-IL-22 or MSA mRNA via intravenous or intramuscular injection. Metabolic markers were monitored for the duration of the experiments, and postmortem histology assessment and analysis of metabolic gene expression pathways were performed. Results: MSA-IL-22 was detectable for ≥8 days following administration. Improvements in body weight, lipid metabolism, glucose metabolism, and lipogenic and fibrotic marker gene expression in the liver were observed in the MSA-IL-22–treated mice, and these effects were shown to be durable. Conclusions: These results support the application of mRNA-encoded IL-22 as a promising treatment strategy for metabolic syndrome and associated comorbidities in human populations.

Atopic dermatitis (AD) is a chronic inflammatory skin disease clinically characterized by eczematous skin manifestations; sometimes it can manifest with non-specific clinical features, in common with other skin conditions, such as infectious and neoplastic diseases. We would like to underline the importance of accurate dermatologic examination and rigorous anamnesis in patient affected by AD, in order to avoid misdiagnosis and delayed treatments.

Objective: To evaluate transperineal laser ablation (TPLA) with Echolaser® (Echolaser® TPLA, Elesta S.p.A., Calenzano, Italy) as a treatment for benign prostatic hyperplasia (BPH) and prostate cancer (PCa) using the Delphi consensus method. Methods: Italian and international experts on BPH and PCa participated in a collaborative consensus project. During two rounds, they expressed their opinions on Echolaser® TPLA for the treatment of BPH and PCa answering online questionnaires on indications, methodology, and potential complications of this technology. Level of agreement or disagreement to reach consensus was set at 75%. If the consensus was not achieved, questions were modified after each round. A final round was performed during an online meeting, in which results were discussed and finalized. Results: Thirty-two out of forty invited experts participated and consensus was reached on all topics. Agreement was achieved on recommending Echolaser® TPLA as a treatment of BPH in patients with ample range of prostate volume, from 80 mL (80%), comorbidities (100%), antiplatelet or anticoagulant treatment (96%), indwelling catheter (77%), and strong will of preserving ejaculatory function (100%). Majority of respondents agreed that Echolaser® TPLA is a potential option for the treatment of localized PCa (78%) and recommended it for low-risk PCa (90%). During the final round, experts concluded that it can be used for intermediate-risk PCa and it should be proposed as an effective alternative to radical prostatectomy for patients with strong will of avoiding urinary incontinence and sexual dysfunction. Almost all participants agreed that the transperineal approach of this organ-sparing technique is safer than transrectal and transurethral approaches typical of other techniques (97% of agreement among experts). Pre-procedural assessment, technical aspects, post-procedural catheterization, pharmacological therapy, and expected outcomes were discussed, leading to statements and recommendations. Conclusion: Echolaser® TPLA is a safe and effective procedure that treats BPH and localized PCa with satisfactory functional and sexual outcomes.

Abstract Background CRISPR/Cas9 system to treat human-related diseases has achieved significant results and, even if its potential application in cancer research is improving, the application of this approach in clinical practice is still a nascent technology. Main body CRISPR/Cas9 technology is not yet used as a single therapy to treat tumors but it can be combined with traditional treatment strategies to provide personalized gene therapy for patients. The combination with chemotherapy, radiation and immunotherapy has been proven to be a powerful means of screening, identifying, validating and correcting tumor targets. Recently, CRISPR/Cas9 technology and CAR T-cell therapies have been integrated to open novel opportunities for the production of more efficient CAR T-cells for all patients. GMP-compatible equipment and reagents are already available for several clinical-grade systems at present, creating the basis and framework for the accelerated development of novel treatment methods. Conclusion Here we will provide a comprehensive collection of the actual GMP-grade CRISPR/Cas9-mediated approaches used to support cancer therapy highlighting how this technology is opening new opportunities for treating tumors.

Hericium erinaceus (Lion’s Mane mushroom) is widely consumed for its numerous reported benefits for brain health. A growing body of evidence suggests that these benefits are likely attributable to aromatic compounds contained in its fruiting bodies, including the meroterpenoids hericenones. Here, we report the identification and reconstitution of the first two steps of the biosynthetic pathway of hericenones via heterologous expression of the polyketide synthase HerA and the carboxylic acid reductase HerB in Aspergillus oryzae. Furthermore, we investigated a putative prenyltransferase that might be responsible for the following biosynthetic step. Ongoing efforts to reconstitute the full pathway will enable large-scale production of hericenones and other meroterpenoids in heterologous hosts.

Summary: Background: Mucositis is a common and highly impactful side effect of conventional and emerging cancer therapy and thus the subject of intense investigation. Although common practice, mucositis assessment is heterogeneously adopted and poorly guided, impacting evidence synthesis and translation. The Multinational Association of Supportive Care in Cancer (MASCC) Mucositis Study Group (MSG) therefore aimed to establish expert recommendations for how existing mucositis assessment tools should be used, in clinical care and trials contexts, to improve the consistency of mucositis assessment. Methods: This study was conducted over two stages (January 2022–July 2023). The first phase involved a survey to MASCC-MSG members (January 2022–May 2022), capturing current practices, challenges and preferences. These then informed the second phase, in which a set of initial recommendations were prepared and refined using the Delphi method (February 2023–May 2023). Consensus was defined as agreement on a parameter by >80% of respondents. Findings: Seventy-two MASCC-MSG members completed the first phase of the study (37 females, 34 males, mainly oral care specialists). High variability was noted in the use of mucositis assessment tools, with a high reliance on clinician assessment compared to patient reported outcome measures (PROMs, 47% vs 3%, 37% used a combination). The World Health Organization (WHO) and Common Terminology Criteria for Adverse Events (CTCAE) scales were most commonly used to assess mucositis across multiple settings. Initial recommendations were reviewed by experienced MSG members and following two rounds of Delphi survey consensus was achieved in 91 of 100 recommendations. For example, in patients receiving chemotherapy, the recommended tool for clinician assessment in clinical practice is WHO for oral mucositis (89.5% consensus), and WHO or CTCAE for gastrointestinal mucositis (85.7% consensus). The recommended PROM in clinical trials is OMD/WQ for oral mucositis (93.3% consensus), and PRO-CTCAE for gastrointestinal mucositis (83.3% consensus). Interpretation: These new recommendations provide much needed guidance on mucositis assessment and may be applied in both clinical practice and research to streamline comparison and synthesis of global data sets, thus accelerating translation of new knowledge into clinical practice. Funding: No funding was received.

Objectives: Post-stroke fatigue (PSF) is an experience characterized by an early feeling of exhaustion with fatigue, a lack of energy, and difficulty in exertion, both motor and cognitive. To counteract fatigue and limit its effects on activities of daily living, the use of vitamins and minerals is known in addition to the pharmacological approach. However, few studies have evaluated the effect of vitamin and mineral supplementation on fatigue management. SiderAL® Med is a food for special medical purposes with a complete formulation containing vitamins, sucrosomal minerals, copper and algal calcium. The aim of the study is to evaluate whether nutritional supplementation with SiderAL® Med improves the symptom of fatigue and motor and cognitive function in stroke patients. Design: This is a pilot, randomized study with a control group. Setting: Post-Acute Rehabilitation Unit of the Fondazione Policlinico “A. Gemelli” IRCCS. Participants: Twenty-four patients with stroke outcomes, admitted to rehabilitation, were recruited and randomized into the experimental group (Sid-G) and the control group (CG). Intervention: The Sid-G patients, in association with the pharmacological and rehabilitation therapy foreseen during hospitalization, took SiderAL® Med, one sachet per day for 8 weeks, while the CG patients underwent only the pharmacological and rehabilitation therapy foreseen in the daily routine. Measurements: All patients were assessed at baseline (T0), after 4 weeks (T1), after 8 weeks (T2) and after 12 weeks (T3) for motor and cognitive fatigue, balance, walking, functional capacity, cognitive performance, autonomy, quality of life and body composition. Results: Both Sid-G and CG patients showed significant improvement on most rating scales between T0-T1-T2-T3 (p = 0.0001). When comparing the two groups, a statistically significant difference emerged in favor of Sid-G with regard to motor fatigue (p = 0.007), cognitive fatigue (p = 0.009) and total fatigue (p = 0.034); balance (p < 0.001), functional capacity (p < 0.001); cognitive performance (p = 0.004); bone mineral content (p = 0.005), lean mass (p = 0.005), total mass (p < 0.001) and percentage of fat mass (p = 0.039). Conclusion: Nutritional supplementation with SiderAL® Med, in concert with intensive rehabilitation treatment, appears to be effective in managing fatigue and improving motor and cognitive performance and body composition, representing a valuable tool to associate with rehabilitation treatment in stroke patients.

Aim:: Intravesical onabotulinum toxin A (BTX) injection is a widely recognized treatment for idiopathic detrusor overactivity (DO) and neurogenic detrusor overactivity (NDO) refractory to adjustments in oral medications.The primary end point of our study was to evaluate patients’ comfort and tolerability with intravesical BTX treatment given in an office-based setting inside a hospital. As a secondary end point, for a subgroup of patients who had previously undergone the procedure in an operating room, we aimed to ascertain if there was any difference in patients’ preferences between the office and operating room settings. Methods:: A cross-sectional descriptive study was designed to evaluate patients’ comfort and tolerability with intravesical BTX treatment given in an office-based setting. It was based on a questionnaire investigating the patients’ overall experience during the procedure and subsequent recovery. Results:: A total of 74 consecutive patients treated between January 2016 and July 2022 were enrolled: 48 males and 26 females; the average age was 57.09 years, ranging from 23–84 years. Among them, 66.2% presented with NDO, and 33.8% with DO. Conclusions:: According to our study, intravesical BTX injections in an office-based setting inside a hospital appear to be a well-tolerated procedure. Most of the patients in our study who experienced both options finally preferred the office setting rather than the operating room. This is an important result, especially if we consider that most patients are required to repeat the treatment over time.

IntroductionThe emergence of drug-resistant Mycobacterium tuberculosis (Mtb) strains has underscored the urgent need for novel therapeutic approaches. Carbon-based nanomaterials, such as graphene oxide (GO), have shown potential in anti-TB activities but suffer from significant toxicity issues.MethodsThis study explores the anti-TB potential of differently functionalized graphene quantum dots (GQDs) – non-functionalized, L-GQDs, aminated (NH2-GQDs), and carboxylated (COOH-GQDs) – alone and in combination with standard TB drugs (isoniazid, amikacin, and linezolid). Their effects were assessed in both axenic cultures and in vitro infection models.ResultsGQDs alone did not demonstrate direct mycobactericidal effects nor trapping activity. However, the combination of NH2-GQDs with amikacin significantly reduced CFUs in in vitro models. NH2-GQDs and COOH-GQDs also enhanced the antimicrobial activity of amikacin in infected macrophages, although L-GQDs and COOH-GQDs alone showed no significant activity.DiscussionThe results suggest that specific types of GQDs, particularly NH2-GQDs, can enhance the efficacy of existing anti-TB drugs. These nanoparticles might serve as effective adjuvants in anti-TB therapy by boosting drug performance and reducing bacterial counts in host cells, highlighting their potential as part of advanced drug delivery systems in tuberculosis treatment. Further investigations are needed to better understand their mechanisms and optimize their use in clinical settings.

Abstract Malva sylvestris L. (common mallow) is a plant species widely used in phytotherapy and ethnobotanical practices since time immemorial. Characterizing the components of this herb might promote a better comprehension of its biological effects on the human body but also favour the identification of the molecular processes that occur in the plant tissues. Thus, in the present contribution, the scientific knowledge about the metabolomic profile of the common mallow was expanded. In particular, the phytocomplex of leaves and flowers from this botanical species and the extraction capacity of different concentrations of ethanol (i.e., 95%, 70%, 50%, and 0%; v/v in ddH2O) for it were investigated by spectrophotometric and chromatographic approaches. In detail, 95% ethanol extracts showed the worst capacity in isolating total phenols and flavonoids, while all the hydroalcoholic samples revealed a specific ability in purifying the anthocyanins. HPLC–DAD system detected and quantified 20 phenolic secondary metabolites, whose concentration in the several extracts depended on their own chemical nature and the percentage of ethanol used in the preparation. In addition, the stability of the purified phytochemicals after resuspension in pure ddH2O was also proved, considering a potential employment of them in biological/medical studies which include in vitro and in vivo experiments on mammalian models. Here, for the first time, the expressed miRNome in M. sylvestris was also defined by Next Generation Sequencing, revealing the presence of 33 microRNAs (miRNAs), 10 typical for leaves and 2 for flowers. Then, both plant and human putative mRNA targets for the detected miRNAs were predicted by bioinformatics analyses, with the aim to clarify the possible role of these small nucleic acids in the common mallow plant tissues and to try to understand if they could exert a potential cross-kingdom regulatory activity on the human health. Surprisingly, our investigations revealed that 19 miRNAs out of 33 were putatively able to modulate, in the plant cells, the expression of various chromosome scaffold proteins. In parallel, we found, in the human transcriptome, a total of 383 mRNAs involved in 5 fundamental mammalian cellular processes (i.e., apoptosis, senescence, cell-cycle, oxidative stress, and invasiveness) that theoretically could be bound and regulated by M. sylvestris miRNAs. The evidence collected in this work would suggest that the beneficial properties of the use of M. sylvestris, documented by the folk medicine, are probably linked to their content of miRNAs and not only to the action of phytochemicals (e.g., anthocyanins). This would open new perspectives about the possibility to develop gene therapies based on miRNAs isolated from medicinal plants, including M. sylvestris.

Background: Radiation therapy (RT) is a mainstay for the treatment of head and neck (HN) cancers, with 80% of patients receiving such treatment. Radiation-induced malignancies represent a life-threatening long-term effect of RT, with an incidence of 0.5% to 15%. Case Description: After 13 years, a 33-year-old woman treated with chemo-radiotherapy for nasopharyngeal carcinoma developed a locally advanced, radiation-induced, p16-negative oropharyngeal squamous cell carcinoma (SCC) at the base of the tongue. Chemo/immunotherapy was administered as a first-line treatment. Given the optimal response and the feasibility of surgery, after three cycles, the patient underwent a total glossectomy, bilateral neck dissection, and reconstruction with a thoraco-dorsal free flap. A histological examination found SCC with a residual cancer burden of 70% and free margins. Discussion: The mechanisms responsible for carcinogenesis after RT are still not completely clear. Diagnosis may be challenging due to the previous treatment; growth patterns are unusual, and lymphotropism is lower. Prognosis is usually poor since surgical resectability is often not achievable. Conclusions: Radiation-induced malignancies are difficult to treat. Patient management should always be discussed at a multidisciplinary level. Future research is needed to assess whether the promising results of clinical studies with pre-operative immunotherapy in locally advanced HN SCC patients may be translated into radiation-induced cancers.

Desert strains of the genus Chroococcidiopsis are among the most desiccation-resistant cyanobacteria capable of anhydrobiosis. The accumulation of two sugars, sucrose and trehalose, facilitates the entrance of anhydrobiotes into a reversible state of dormancy by stabilizing cellular components upon water removal. This study aimed to evaluate, at the atomistic level, the role of trehalose in desiccation resistance by using as a model system the 30S ribosomal subunit of the desert cyanobacterium Chroococcidiopsis sp. 029. Molecular dynamic simulations provided atomistic evidence regarding its protective role on the 30S molecular structure. Trehalose forms an enveloping shell around the ribosomal subunit and stabilizes the structures through a network of direct interactions. The simulation confirmed that trehalose actively interacts with the 30S ribosomal subunit and that, by replacing water molecules, it ensures ribosomal structural integrity during desiccation, thus enabling protein synthesis to be carried out upon rehydration.

Abstract Background NUT carcinoma (NUTc) is a rare and aggressive malignant epithelial tumor characterized by rearrangement of the NUT gene on chromosome 15q14. Methods In this article, we present the fifth case worldwide of a young woman affected by a NUTc arising from a submandibular gland, presenting as a rapidly evolving mass. She underwent a right scialoadenectomy and received the initial diagnosis of high‐grade mucoepidermoid carcinoma. Due to evidence of local recurrence at magnetic resonance imaging 1 month later, a subsequent right radical neck dissection was performed. The patient then sought a second opinion at our cancer center and finally received the correct diagnosis of NUT carcinoma. Given the well‐known aggressive behavior of this neoplasm, as well as clinical and radiological features, she underwent adjuvant chemo‐radiation (intensity‐modulated radiotherapy + concurrent chemotherapy with cisplatin). Results After a disease‐free interval of 2.6 months, a widespread metastatic disease led to rapid deterioration of performance status and patient death in a few weeks after metastatic onset. Conclusions We presented a case of NUTc arising from salivary gland aiming to improve the knowledge of this rare malignancy. First, we pointed out that in the setting of rare tumors like salivary gland cancers, the diagnosis should be obtained by expert pathologists, and patients should be referred to tertiary cancer centers for their clinical management. Second, molecular profiling may help to identify possible druggable targets that may be exploited to treat patients suffering from this aggressive malignancy. Sharing the molecular data provided in this case will be useful for further research.

BackgroundPregnancy-associated cancer (PAC) occurs during pregnancy or within 12 months after the delivery. Head and neck cancer (HNC) during pregnancy is infrequent, therefore diagnosis and personalized therapy are intricate.MethodsWe investigated outcomes of 15 PAC patients (5 salivary, 4 nasopharyngeal, 3 thyroid, 2 oral cavity, one HPV-related carcinoma) diagnosed in the period 2005-2019. A literature review on PAC is provided.ResultsMedian gestational age at PAC diagnosis was 28 weeks (range: 16–40 weeks) in ten cases, at 5 months after delivery (range: 1 week–6 months) in the remaining five. Treatments included surgery (3 during pregnancy, 5 after childbirth), chemoradiation (8), and 3 patients with upfront metastatic disease received chemotherapy. Median survival was 6.6 years (eight women remain with no evidence of disease six years after diagnosis).ConclusionAll patients received state-of-the-art therapy, with encouraging long-term results, highlighting treatment safety in women with HNC during pregnancy.