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Fasting mimicking diets (FMDs) are effective in the treatment of many solid tumors in mouse models, but their effect on hematologic malignancies is poorly understood, particularly in combination with standard therapies. Here we show that cycles of a 3-day FMD given to high-fat-diet-fed mice once a week increased the efficacy of vincristine to improve survival from BCR-ABL B acute lymphoblastic leukemia (ALL). In mice fed a standard diet, FMD cycles in combination with vincristine promoted cancer-free survival. RNA seq and protein assays revealed a vincristine-dependent decrease in the expression of multiple autophagy markers, which was exacerbated by the fasting/FMD conditions. The autophagy inhibitor chloroquine could substitute for fasting/FMD to promote cancer-free survival in combination with vincristine. In vitro, targeted inhibition of autophagy genes ULK1 and ATG9a strongly potentiated vincristines toxicity. Moreover, anti-CD8 antibodies reversed the effects of vincristine plus fasting/FMD in promoting leukemia-free survival in mice, indicating a central role of the immune system in this response. Thus, the inhibition of autophagy and enhancement of immune responses appear to be mediators of the fasting/FMD-dependent cancer-free survival in ALL mice.

Abstract After recasting the standard charged and uncharged brane profiles in the harmonic gauge, we explore solutions with the same isometries where the potentials V = T e γ ϕ of ten-dimensional non-supersymmetric strings are taken into account. Combining a detailed catalog of the possible asymptotics with some numerical results suggests that these spherically symmetric backgrounds terminate at singularities within finite proper distances.

Abstract The pathophysiological mechanisms of cardiovascular disease and microvascular complications in diabetes have been extensively studied, but effective methods of prevention and treatment are still lacking. In recent years, DNA methylation, histone modifications, and non-coding RNAs have arisen as possible mechanisms involved in the development, maintenance, and progression of micro- and macro-vascular complications of diabetes. Epigenetic changes have the characteristic of being heritable or deletable. For this reason, they are now being studied as a therapeutic target for the treatment of diabetes and the prevention or for slowing down its complications, aiming to alleviate the personal and social burden of the disease. This review addresses current knowledge of the pathophysiological links between diabetes and cardiovascular complications, focusing on the role of epigenetic modifications, including DNA methylation and histone modifications. In addition, although the treatment of complications of diabetes with “epidrugs” is still far from being a reality and faces several challenges, we present the most promising molecules and approaches in this field.

Abstract We connect the indications of 2D CFT for branes in non-supersymmetric strings to actual spacetime profiles, taking the bulk tadpole potentials into account. We find exact solutions for the uncharged branes that spread in the internal intervals of Dudas-Mourad vacua for non-tachyonic orientifolds and heterotic strings. These solutions involve suitable dressings of the uncharged branes of the nine-dimensional tadpole-free theory. Similar exact results for uncharged branes that are transverse to the internal space, or for charged branes, appear more challenging. Nevertheless, we identify their large-distance behavior, which is determined by linearized equations, and show that it is compatible with the CFT analysis in all expected cases. We also provide some hints on the leading back-reaction of the form-fields.

Small interfering RNA (siRNA) is essential for the process of gene silencing, especially for cancer. Despite its considerable promise, siRNA faces challenges due to stability issues of formulation and undesirable off-target side effects. In order to address these difficulties, it is essential to carefully monitor the levels of siRNA. The existing point-of-care (POC) systems cannot precisely and efficiently detect or monitor siRNA levels. In light of these challenges, this review gives the prospects of siRNA detection by proposing a novel hypothesis of existing electrical and optical-based detection of DNA/RNA with the POC platform. This hypothesis offers an interesting novel perspective to potentially fill the existing gaps, in detecting siRNA. By utilising these technologies, there is high potential to develop a proof-of-concept system that will not only overcome the existing challenges, but it will also allow effective and precise monitoring of siRNA, in real-world healthcare environments. In summary, the prospects for siRNA in the realm of POC platforms are quite encouraging, since it allows precise and effective monitoring.

Abstract Febrile seizures (FS) are commonly perceived by healthcare professionals as a self-limited condition with a generally ‘benign’ nature. Nonetheless, they frequently lead to pediatric consultations, and their management can vary depending on the clinical context. For parents and caregivers, witnessing a seizure can be a distressing experience, significantly impacting their quality of life. In this review, we offer an in-depth exploration of FS management, therapeutic interventions, and prognostic factors, with the aim of providing support for physicians and enhancing communication with families. We conducted a comprehensive literature search using the PubMed and Web of Science databases, spanning the past 50 years. The search terms utilized included “febrile seizure,” “complex febrile seizure,” “simple febrile seizure,” in conjunction with “children” or “infant.” Only studies published in English or those presenting evidence-based data were included in our assessment. Additionally, we conducted a cross-reference search to identify any additional relevant data sources. Our thorough literature search resulted in a compilation of references, with carefully selected papers thoughtfully integrated into this review.

Recently, the term theragenerative has been proposed for biomaterials capable of inducing therapeutic approaches followed by repairing/regenerating the tissue/organ. This study is focused on the design of a new theragenerative nanocomposite composed of an amphiphilic non-ionic surfactant (Pluronic F127), bioactive glass (BG), and black phosphorus (BP). The nanocomposite was prepared through a two-step synthetic strategy, including a microwave treatment that turned BP nanosheets (BPNS) into quantum dots (BPQDs) with 5 ± 2 nm dimensions in situ. The effects of surfactant and microwave treatment were assessed in vitro: the surfactant distributes the ions homogenously throughout the composite and the microwave treatment chemically stabilizes the composite. The presence of BP enhanced bioactivity and promoted calcium phosphate formation in simulated body fluid. The inherent anticancer activity of BP-containing nanocomposites was tested against osteosarcoma cells in vitro, finding that 150 μg mL−1 was the lowest concentration which prevented the proliferation of SAOS-2 cells, while the counterpart without BP did not affect the cell growth rate. Moreover, the apoptosis pathways were evaluated and a mechanism of action was proposed. NIR irradiation was applied to induce further proliferation suppression on SAOS-2 cells through hyperthermia. The inhibitory effects of bare BP nanomaterials and nanocomposites on the migration and invasion of bone cancer, breast cancer, and prostate cancer cells were assessed in vitro to determine the anticancer potential of nanomaterials against primary and secondary bone cancers. The regenerative behavior of the nanocomposites was tested with healthy osteoblasts and human mesenchymal stem cells; the BPQDs-incorporated nanocomposite significantly promoted the proliferation of osteoblast cells and induced the osteogenic differentiation of stem cells. This study introduces a new multifunctional theragenerative platform with promising potential for simultaneous bone cancer therapy and regeneration.

Abstract Background To date, the etiology and risk factors of torticollis are still poorly defined in the pediatric literature. Especially in the Emergency Department (ED) scenario, it is critical to reliably distinguish benign and transient conditions from (potentially) life-threatening disorders. This study describes the clinical characteristics of a large sample of children with torticollis. The aim of our study was to detect epidemiology, etiology and predictive variables associated with a higher risk of life-threatening conditions in acute torticollis. Methods We conducted a pediatric retrospective study of acute torticollis over a 13-year period referred to the ED of a tertiary pediatric Hospital. We reported the characteristics in the overall sample and in two subgroups divided according to urgency of the underlying condition. Furthermore, we developed a multivariate model aimed at identifying the main clinical predictors of the need for urgent care. Results 1409 patients were analyzed (median age 5.7 years, IQR 5.8). A history of trauma was present in 393 patients (27.9%). The symptom most frequently associated with torticollis were pain (83.5%). At least one pathological finding was found in 5.4 to 7.9% of patients undergoing further imaging. Hospitalization was required in 11.1% of cases (median duration 4 days). The most frequent etiologies of torticollis were postural cause (43.1%), traumatic (29.5%), and infective/inflammatory (19.1%). A longer time from onset of torticollis and the presence of headache or vomiting were strongly correlated with an underlying urgent condition, after adjusting for the other clinically and statistically significant variables in the bivariate analysis. Conclusion Our study shows that an urgent condition most commonly occur in patients presenting with history of trauma or headache, vomiting and torticollis for more than 24 h should undergo further diagnostic evaluation and short-term follow-up, restricting invasive or expensive investigations to patients with clinical suspicion of an underlying harmful condition.

Abstract Background Diabetes-induced trained immunity contributes to the development of atherosclerosis and its complications. This study aimed to investigate in humans whether epigenetic signals involved in immune cell activation and inflammation are initiated in hematopoietic stem/progenitor cells (HSPCs) and transferred to differentiated progeny. Methods and results High glucose (HG)-exposure of cord blood (CB)-derived HSPCs induced a senescent-associated secretory phenotype (SASP) characterized by cell proliferation lowering, ROS production, telomere shortening, up-regulation of p21 and p27genes, upregulation of NFkB-p65 transcription factor and increased secretion of the inflammatory cytokines TNFα and IL6. Chromatin immunoprecipitation assay (ChIP) of p65 promoter revealed that H3K4me1 histone mark accumulation and methyltransferase SetD7 recruitment, along with the reduction of repressive H3K9me3 histone modification, were involved in NFkB-p65 upregulation of HG-HSPCs, as confirmed by increased RNA polymerase II engagement at gene level. The differentiation of HG-HSPCs into myeloid cells generated highly responsive monocytes, mainly composed of intermediate subsets (CD14hiCD16+), that like the cells from which they derive, were characterized by SASP features and similar epigenetic patterns at the p65 promoter. The clinical relevance of our findings was confirmed in sternal BM-derived HSPCs of T2DM patients. In line with our in vitro model, T2DM HSPCs were characterized by SASP profile and SETD7 upregulation. Additionally, they generated, after myeloid differentiation, senescent monocytes mainly composed of proinflammatory intermediates (CD14hiCD16+) characterized by H3K4me1 accumulation at NFkB-p65 promoter. Conclusions Hyperglycemia induces marked chromatin modifications in HSPCs, which, once transmitted to the cell progeny, contributes to persistent and pathogenic changes in immune cell function and composition.

Abstract Despite progress in the prevention and diagnosis of cancer, current technologies for tumor detection present several limitations including invasiveness, toxicity, inaccuracy, lengthy testing duration and high cost. Therefore, innovative diagnostic techniques that integrate knowledge from biology, oncology, medicinal and analytical chemistry are now quickly emerging in the attempt to address these issues. Following this approach, here we developed a paper-based electrochemical device for detecting cancer-derived Small Extracellular Vesicles (S-EVs) in fluids. S-EVs were obtained from cancer cell lines known to express, at a different level, the αvβ6 integrin receptor, a well-established hallmark of numerous epithelial cancer types. The resulting biosensor turned out to recognize αvβ6-containing S-EVs down to a limit of 0.7*103 S-EVs/mL with a linear range up to 105 S-EVs /mL, and a relative standard deviation of 11%, thus it may represent a novel opportunity for αvβ6 expressing cancers detection.

Abstract The growth of liquid biopsy, i. e., the possibility of obtaining health information by analysing circulating species (nucleic acids, cells, proteins, and vesicles) in peripheric biofluids, is pushing the field of sensors and biosensors beyond the limit to provide decentralised solutions for nonspecialists. In particular, among all the circulating species that can be adopted in managing cancer evolution, both for diagnostic and prognostic applications, microRNAs have been highly studied and detected. The development of electrochemical devices is particularly relevant for liquid biopsy purposes, and the screen‐printed electrodes (SPEs) represent one of the building blocks for producing novel portable devices. In this work, we have taken miR‐2115‐3p as model target (it is related to lung cancer), and we have developed a biosensor by exploiting the use of a complementary DNA probe modified with methylene blue as redox mediator. In particular, the chosen sensing architecture was applied to serum measurements of the selected miRNA, obtaining a detection limit within the low nanomolar range; in addition, various platforms were interrogated, namely commercial and hand‐made SPEs, with the aim of providing the reader with some insights about the optimal platform to be used by considering both the cost and the analytical performance.