Search

How hematopoietic stem and progenitor cell (HSPC) fate decisions are affected by genetic alterations acquired during AML leukemogenesis is poorly understood and mainly explored in animal models. Here, we study isocitrate dehydrogenase ( IDH ) gene mutations in the human model of HSPC and discuss the available literature on this topic. IDH1/2 mutations occur in ~20% of AML cases, are recognized among the mutations earliest acquired during leukemogenesis, and are targets of specific inhibitors (ivosidenib and enasidenib, respectively). In order to investigate the direct effects of these mutations on HSPCs, we expressed IDH1 -R132H or IDH2 -R140Q mutants into human CD34+ healthy donor cells via lentiviral transduction and analyzed the colony-forming unit (CFU) ability. CFU ability was dramatically compromised with a complete trilineage block of differentiation. Strikingly, the block was reversed by specific inhibitors, confirming that it was a specific effect induced by the mutants. In line with this observation, the CD34+ leukemic precursors isolated from a patient with IDH2 -mutated AML at baseline and during enasidenib treatment showed progressive and marked improvements in their fitness over time, in terms of CFU ability and propensity to differentiate. They attained clonal trilinear reconstitution of hematopoiesis and complete hematological remission.

Photodynamic therapy (PDT) is a therapeutic option for cancer, in which photosensitizer (PS) drugs, light, and molecular oxygen generate reactive oxygen species (ROS) and induce cell death. First- and second-generation PSs presented with problems that hindered their efficacy, including low solubility. Thus, second-generation PSs loaded into nanocarriers were produced to enhance their cellular uptake and therapeutic efficacy. Among other compounds investigated, the dye methylene blue (MB) showed potential as a PS, and its photodynamic activity in tumor cells was reported even in its nanocarrier-delivered form, including liposomes. Here, we prepared polydopamine (PDA)-coated liposomes and efficiently adsorbed MB onto their surface. lipoPDA@MB vesicles were first physico-chemically characterized and studies on their light stability and on the in vitro release of MB were performed. Photodynamic effects were then assessed on a panel of 2D- and 3D-cultured cancer cell lines, comparing the results with those obtained using free MB. lipoPDA@MB uptake, type of cell death induced, and ability to generate ROS were also investigated. Our results show that lipoPDA@MB possesses higher photodynamic potency compared to MB in both 2D and 3D cell models, probably thanks to its higher uptake, ROS production, and apoptotic cell death induction. Therefore, lipoPDA@MB appears as an efficient drug delivery system for MB-based PDT.

This paper addresses indoor localization using an anchor-based system based on Bluetooth Low Energy (BLE) 5.0 technology, adopting the Received Signal Strength Indicator (RSSI) for the distance estimation. Different solutions have been proposed in the scientific literature to improve the performance of this localization technology, but a detailed performance comparison of these solutions is still missing. The aim of this work is to make an experimental analysis combining different solutions for the performance improvement of BLE-based indoor localization, identifying the most effective one. The considered solutions involve different RSSI signals' conditioning, the use of anchor-tag distance estimation techniques, as well as approaches for estimating the unknown tag position. An experimental campaign was executed in a complex indoor environment, characterized by the continuous presence in the movement of working staff and numerous obstacles. The exploitation of multichannel transmission using RSSI signal aggregation techniques showed the greater performance improvement of the localization system, reducing the positioning error (from 1.5 m to about 1 m). The other examined solutions have shown a lesser impact in the performance improvement with a decrease or an increase in the positioning errors, depending on the considered combination of the adopted solutions.

Freeze-dried chitosan formulations solubilized in platelet-rich plasma (PRP) are currently evaluated as injectable implants with the potential for augmenting the standard of care for tissue repair in different orthopedic conditions. The present study aimed to shorten the solidification time of such implants, leading to an easier application and a facilitated solidification in a wet environment, which were direct demands from orthopedic surgeons. The addition of thrombin to the formulation before lyophilization was explored. The challenge was to find a formulation that coagulated fast enough to be applied in a wet environment but not too fast, which would make handling/injection difficult. Four thrombin concentrations were analyzed (0.0, 0.25, 0.5, and 1.0 NIH/mL) in vitro (using thromboelastography, rheology, indentation, syringe injectability, and thrombin activity tests) as well as ex vivo (by assessing the implant's adherence to tendon tissue in a wet environment). The biomaterial containing 0.5 NIH/mL of thrombin significantly increased the coagulation speed while being easy to handle up to 6 min after solubilization. Furthermore, the adherence of the biomaterial to tendon tissues was impacted by the biomaterial-tendon contact duration and increased faster when thrombin was present. These results suggest that our biomaterial has great potential for use in regenerative medicine applications.

Gelatin is a highly versatile natural polymer, which is widely used in healthcare-related sectors due to its advantageous properties, such as biocompatibility, biodegradability, low-cost, and the availability of exposed chemical groups. In the biomedical field, gelatin is used also as a biomaterial for the development of drug delivery systems (DDSs) due to its applicability to several synthesis techniques. In this review, after a brief overview of its chemical and physical properties, the focus is placed on the commonly used techniques for the development of gelatin-based micro- or nano-sized DDSs. We highlight the potential of gelatin as a carrier of many types of bioactive compounds and its ability to tune and control select drugs' release kinetics. The desolvation, nanoprecipitation, coacervation, emulsion, electrospray, and spray drying techniques are described from a methodological and mechanistic point of view, with a careful analysis of the effects of the main variable parameters on the DDSs' properties. Lastly, the outcomes of preclinical and clinical studies involving gelatin-based DDSs are thoroughly discussed.

Cancer patients are at an increased risk of developing severe consequences due to the COVID-19 infection. However, psychological outcomes in this population have been overlooked in the literature. The present study aims to identify significant psychological differences between gynecological cancer patients undergoing chemotherapy before and during the pandemic. Additionally, we explore the correlations between COVID-19-related concerns and anxiety, depression, distress, and quality of life levels. Forty-two patients completed the STAI-Y, the EORTC QLQ-C30, the BDI II, the DT, and an ad-hoc questionnaire that investigated COVID-19-related concerns. The analyses did not show significant differences in the psychometric scales between the two groups, highlighting a considerable resilience against mental health and quality of life deterioration during the COVID-19 pandemic in gynecologic cancer patients. However, COVID-19-related concerns were positively associated with anxiety and inversely related to emotional functioning levels. These results emphasize the importance of a comprehensive patient care and the need to implement a multidisciplinary approach that includes psychological support in the treatment plan. Moreover, it is essential to encourage clear communication to convey comprehensive information about the impact of the pandemic on physical and psychological levels, as well as to offer psychoeducational tools to face the pandemic., Competing Interests: The authors declare no conflict of interest.

Acute myeloid leukemia (AML) is a heterogeneous hematopoietic malignancy whose prognosis is globally poor. In more than 60% of AML patients, the PI3K/AKTs/mTOR signaling pathway is aberrantly activated because of oncogenic driver alterations and further enhanced by chemotherapy as a mechanism of drug resistance. Against this backdrop, very recently we have started a multidisciplinary research project focused on AKT1 as a pharmacological target to identify novel anti-AML agents. Indeed, the serendipitous finding of the in-house compound T187 as an AKT1 inhibitor has paved the way to the rational identification of new active small molecules, among which T126 has emerged as the most interesting compound with IC 50 = 1.99 ± 0.11 μM, ligand efficiency of 0.35, and a clear effect at low micromolar concentrations on growth inhibition and induction of apoptosis in AML cells. The collected results together with preliminary SAR data strongly indicate that the 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3- d ]pyrimidin-4(3 H )-one derivative T126 is worthy of future biological experiments and medicinal chemistry efforts aimed at developing a novel chemical class of AKT1 inhibitors as anti-AML agents.

The administration of combinations of drugs is a method widely used in the treatment of different pathologies as it can lead to an increase in the therapeutic effect and a reduction in the dose compared to the administration of single drugs. For these reasons, it is of interest to study combinations of drugs and to determine whether a specific combination has a synergistic, antagonistic or additive effect. Various mathematical models have been developed, which use different methods to evaluate the synergy of a combination of drugs. We have developed an open access and easy to use app that allows different models to be explored and the most fitting to be chosen for the specific experimental data: SiCoDEA (Single and Combined Drug Effect Analysis). Despite the existence of other tools for drug combination analysis, SiCoDEA remains the most complete and flexible since it offers options such as outlier removal or the ability to choose between different models for analysis. SiCoDEA is an easy to use tool for analyzing drug combination data and to have a view of the various steps and offer different results based on the model chosen.

Reliable diagnosis of early-stage Parkinson's disease is an important task, since it permits the administration of a timely treatment, slowing the progression of the disease. Together with non-motor symptoms, other important signs of disease can be retrieved from the measurement of the movement trajectory and from tremor appearances. To measure these signs, the paper proposes a magnetic tracking system able to collect information about translational and vibrational movements in a spatial cubic domain, using a low-cost, low-power and highly accurate solution. These features allow the usage of the proposed technology to realize a portable monitoring system, that may be operated at home or in general practices, enabling telemedicine and preventing saturation of large neurological centers. Validation is based on three tests: movement trajectory tracking, a rest tremor test and a finger tapping test. These tests are considered in the Unified Parkinson's Disease Rating Scale and are provided as case studies to prove the system's capabilities to track and detect tremor frequencies. In the case of the tapping test, a preliminary classification scheme is also proposed to discriminate between healthy and ill patients. No human patients are involved in the tests, and most cases are emulated by means of a robotic arm, suitably driven to perform required tasks. Tapping test results show a classification accuracy of about 93% using a k-NN classification algorithm, while imposed tremor frequencies have been correctly detected by the system in the other two tests.

During the last year, the COVID-19 outbreak put all the healthcare workers around the world at risk of physical and psychological sequelae. The general purpose of the present study was to assess the mental health of Italian healthcare workers during the COVID-19 outbreak and to identify high-risk groups. Here, we present results from the baseline assessment of the "Healthcare workers' wellbeing (Benessere Operatori)" project on a sample of 1055 healthcare workers. Participants completed the Depression Anxiety Stress Scale-21, the Insomnia Severity Index, the Impact of Event Scale-Revised, the State-Trait Anger Expression Inventory-2, and the Maslach Burnout Inventory. Healthcare workers who worked in COVID wards reported higher levels of anxiety, insomnia, post-traumatic stress, anger, and burnout, compared to those reported by the healthcare workers who worked in non-COVID wards. Moreover, nurses, both in COVID and non-COVID wards, were at higher risk of experiencing psychological distress compared to other groups of healthcare workers. These findings highlight the importance of implementing targeted psychological interventions for healthcare workers operating in COVID wards and nurses, who seem to be the most vulnerable categories.

Liposomes are consolidated and attractive biomimetic nanocarriers widely used in the field of drug delivery. The structural versatility of liposomes has been exploited for the development of various carriers for the topical or systemic delivery of drugs and bioactive molecules, with the possibility of increasing their bioavailability and stability, and modulating and directing their release, while limiting the side effects at the same time. Nevertheless, first-generation vesicles suffer from some limitations including physical instability, short in vivo circulation lifetime, reduced payload, uncontrolled release properties, and low targeting abilities. Therefore, liposome preparation technology soon took advantage of the possibility of improving vesicle performance using both natural and synthetic polymers. Polymers can easily be synthesized in a controlled manner over a wide range of molecular weights and in a low dispersity range. Their properties are widely tunable and therefore allow the low chemical versatility typical of lipids to be overcome. Moreover, depending on their structure, polymers can be used to create a simple covering on the liposome surface or to intercalate in the phospholipid bilayer to give rise to real hybrid structures. This review illustrates the main strategies implemented in the field of polymer/liposome assembly for drug delivery, with a look at the most recent publications without neglecting basic concepts for a simple and complete understanding by the reader.

Background: Healthcare workers (HCWs) have been the key players in the fight against the coronavirus disease 2019 (COVID-19) pandemic. The aim of our study was to evaluate the seroprevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) IgG anti-bodies., Methods: We conducted a cross-sectional study among workers of two hospitals and Territorial Medical and Administrative services in Northern Italy. From 8 May to 3 June 2020, 2252 subjects were tested. Seroprevalence and 95% confidence interval (CI) were calculated for all individuals who were stratified by job title, COVID-19 risk of exposure, direct contact with patients, unit ward, and intensity of care., Results: Median age was 50 years, and 72% of subjects were female. The overall seroprevalence was 17.11% [95% CI 15.55-18.67]. Around 20% of healthcare assistants were seropositive, followed by physicians and nurses (16.89% and 15.84%, respectively). HCWs with high risk of exposure to COVID-19 were more frequently seropositive (28.52%) with respect to those with medium and low risks (16.71% and 12.76%, respectively). Moreover, personnel in direct contact had higher prevalence (18.32%) compared to those who did not (10.66%). Furthermore, the IgG were more frequently detected among personnel of one hospital (19.43%)., Conclusion: The high seroprevalence observed can be partially explained by the timing and the population seroprevalence; the study was conducted in an area with huge spread of the infection.

NPM1 -mutated ( NPM1 mut) acute myeloid leukemia (AML) comprises about 30% of newly diagnosed AML in adults. Despite notable advances in the treatment of this frequent AML subtype, about 50% of NPM1 mut AML patients treated with conventional treatment die due to disease progression. CD123 has been identified as potential target for immunotherapy in AML, and several anti-CD123 therapeutic approaches have been developed for AML resistant to conventional therapies. As this antigen has been previously reported to be expressed by NPM1 mut cells, we performed a deep flow cytometry analysis of CD123 expression in a large cohort of NPM1 mut and wild-type samples, examining the whole blastic population, as well as CD34 + CD38 - leukemic cells. We demonstrate that CD123 is highly expressed on NPM1 mut cells, with particularly high expression levels showed by CD34 + CD38 - leukemic cells. Additionally, CD123 expression was further enhanced by FLT3 mutations, which frequently co-occur with NPM1 mutations. Our results identify NPM1 -mutated and particularly NPM1/FLT3 double-mutated AML as disease subsets that may benefit from anti-CD123 targeted therapies.

Cellulose nanomaterials have been widely investigated in the last decade, unveiling attractive properties for emerging applications. The ability of sulfated cellulose nanocrystals (CNCs) to guide the supramolecular organization of amphiphilic fullerene derivatives at the air/water interface has been recently highlighted. Here, we further investigated the assembly of Langmuir hybrid films that are based on the electrostatic interaction between cationic fulleropyrrolidines deposited at the air/water interface and anionic CNCs dispersed in the subphase, assessing the influence of additional negatively charged species that are dissolved in the water phase. By means of isotherm acquisition and spectroscopic measurements, we demonstrated that a tetra-sulfonated porphyrin, which was introduced in the subphase as anionic competitor, strongly inhibited the binding of CNCs to the floating fullerene layer. Nevertheless, despite the strong inhibition by anionic molecules, the mutual interaction between fulleropyrrolidines at the interface and the CNCs led to the assembly of robust hybrid films, which could be efficiently transferred onto solid substrates. Interestingly, ITO-electrodes that were modified with five-layer hybrid films exhibited enhanced electrical capacitance and produced anodic photocurrents at 0.4 V vs Ag/AgCl, whose intensity (230 nA/cm 2 ) proved to be four times higher than the one that was observed with the sole fullerene derivative (60 nA/cm 2 ).

Pain is one of the most common symptoms in children suffering from leukemia, who are often misdiagnosed with other childhood painful diseases such as juvenile idiopathic arthritis. Corticosteroid-induced osteonecrosis (ON) and vincristine-induced peripheral neuropathy (VIPN) are the most common painful manifestations. Additionally, ongoing pain may continue to impact quality of life in survivorship. This narrative review focuses on the pathophysiological mechanisms of pain in childhood leukemia and current available indications for analgesic treatments. Pain management in children is often inadequate because of difficulties in pain assessment, different indications across countries, and the lack of specific pediatric trials. Analgesic drugs are often prescribed off-label to children by extrapolating information from adult guidelines, with possible increased risk of adverse events. Optimal pain management should involve a multidisciplinary team to ensure assessment and interventions tailored to the individual patient.

Fruits and vegetables are a good source of potentially biologically active compounds. Their regular consumption in the human diet can help reduce the risk of developing chronic diseases such as cardiovascular diseases and cancer. Plants produce additional chemical substances when subject to abiotic stress or infected by microorganisms. The phytochemical profile of spinach leaves ( Spinacia oleracea L.), which is a vegetable with widely recognized health-promoting activity, has been affected by applying root hypoxic and re-oxygenation stress during plant growth. Leaf juice at different sampling times has been subject to liquid chromatography mass spectrometry (LC-MSn) analysis and tested on the human colorectal adenocarcinoma cell line HT29 by using the Comet assay. The cells were previously treated with H₂O₂ to simulate the presence of an oxidative stress (as in colon cancer condition) and the leaf juice application resulted in a significant antioxidant and protective in vitro effect. The duration of the hypoxic/re-oxygenation stress imposed on the plant reflects the antioxidant leaf juice content. After hypoxic stress (24 hours) and reoxygenation (2 hours), we show a decrease (50%) of the relative abundance of the principal identified antioxidant molecules but a higher antioxidant activity of the spinach juice on HT29 cells (20%). Data shows a complex relation between plant growing conditions and the modulation of secondary metabolites content in leaf juice that results in different chemo-protective activities in colon cancer cells., Competing Interests: The authors declare no conflict of interest.

The present study aimed to develop and optimize liposome formulation for the colonic delivery of biologically active compounds. A strategy to facilitate such targeting is to formulate liposomes with a polymer coating sensitive to the pH shifts in the gastrointestinal tract. To this end, liposomes encapsulating curcumin-chosen as the biologically active compound model-and coated with the pH-responsive polymer Eudragit S100 were prepared and characterized. Curcumin was encapsulated into small unilamellar vesicles (SUVs) by the micelle-to-vesicle transition method (MVT) in a simple and organic solvent-free way. Curcumin-loaded liposomes were coated with Eudragit S100 by a fast and easily scalable pH-driven method. The prepared liposomes were evaluated for size, surface morphology, entrapment efficiency, stability, in vitro drug release, and curcumin antioxidant activity. In particular, curcumin-loaded liposomes displayed size lower than 100 nm, encapsulation efficiency of 98%, high stability at both 4 °C and 25 °C, high in vitro antioxidant activity, and a cumulative release that was completed within 200 min. A good Eudragit S100 coating which did not alter the properties of the curcumin-loaded liposomes was obtained. The present work therefore provides a fast and solvent-free method to prepare pH-responsive polymer-coated liposomes for the colonic delivery of biologically active compounds., Competing Interests: The authors declare no conflict of interest.