First in vivo MRI study on theranostic dendrimersomes

Amphiphilic Janus-dendrimers are able to self-assemble into nanosized vesicles named dendrimersomes.We recently synthesized the 3,5-C12-EG-(OH)4 dendrimer that generates dendrimersomes with very promising safety and stability profiles, that can be loaded with different contrast agents for in vivo imaging. In this contribution, nanovesicles were loaded with both the Magnetic Resonance Imaging (MRI) reporter GdDOTAGA(C18)2 and the glucocorticoid drug Prednisolone Phosphate (PLP), in order to test their effective potential as theranostic nanocarriers on murine melanoma tumour models. The incorporation of GdDOTAGA(C18)2 into the membrane resulted in dendrimersomes with a high longitudinal relaxivity (r1 = 39.1 mM−1 s−1, at 310 K and 40 MHz) so that, after intravenous administration, T1-weighted MRI showed a consistent contrast enhancement in the tumour area. Furthermore, the nanovesicles encapsulated PLP with good efficiency and displayed anti-tumour activity both in vitro and in vivo, thus enabling their practical use for biomedical theranostic applications

Resolvin D1 Halts Remote Neuroinflammation and Improves Functional Recovery after Focal Brain Damage Via ALX/FPR2 Receptor-Regulated MicroRNAs

Remote damage is a secondary phenomenon that usually occurs after a primary brain damage in regions that are distant, yet functionally connected, and that is critical for determining the outcomes of several CNS pathologies, including traumatic brain and spinal cord injuries. The understanding of remote damage-associated mechanisms has been mostly achieved in several models of focal brain injury such as the hemicerebellectomy (HCb) experimental paradigm, which helped to identify the involvement of many key players, such as inflammation, oxidative stress, apoptosis and autophagy. Currently, few interventions have been shown to successfully limit the progression of secondary damage events and there is still an unmet need for new therapeutic options. Given the emergence of the novel concept of resolution of inflammation, mediated by the newly identified ω3-derived specialized pro-resolving lipid mediators, such as resolvins, we reported a reduced ability of HCb-injured animals to produce resolvin D1 (RvD1) and an increased expression of its target receptor ALX/FPR2 in remote brain regions. The in vivo administration of RvD1 promoted functional recovery and neuroprotection by reducing the activation of Iba-1+ microglia and GFAP+ astrocytes as well as by impairing inflammatory-induced neuronal cell death in remote regions. These effects were counteracted by intracerebroventricular neutralization of ALX/FPR2, whose activation by RvD1 also down-regulated miR-146b and miR-219a-1-dependent inflammatory markers. In conclusion, we propose that innovative therapies based on RvD1-ALX/ FPR2 axis could be exploited to curtail remote damage and enable neuroprotective effects after acute focal brain damage

Redox-responsive MRI probes to follow-up hypoxia within cell-embedding hydrogels

*Introduction*In regenerative medicine, biocompatible hydrogels are increasingly used to encapsulate therapeutic cells prior to transplantation into the host to enhance their long term survival. Cell embedding within bioengineered hydrogels can shield cells from immune response and provide an optimal life-sustaining microenvironment to therapeutic cells. In addition, cell embedding offers the outstanding opportunity to insert microenvironment-responsive imaging labels within the hydrogel, paving the way for non-invasive monitoring of the extracellular microenvironment within the hydrogel. We have inserted redox-responsive MRI labels within cell-embedding hydrogels to follow-up the microenvironment redox state.*Methods*High molecular weight chitosan polymers were chemically conjugated with a Gd-HPDO3A-chelate through a disulfide bond, and interspersed within alginate-based hydrogel capsules. Human mesenchymal stem cells (hMSCs) as model therapeutic cells were embedded into such imaging labelled hydrogel. Embedded cells were incubated under simulated hypoxiaconditions, while being followed-up by T1-weighted MRI at 7T.*Results*Under reducing conditions, reductive cleavage of the disulfide bond in the Gd-chitosan probe yields a low molecular weight Gd-chelate that eventually diffuses out of the hydrogel capsule. The resulting change of MRI contrast enhancement along time is very sensitive to the oxygenation level within cell capsules. The kinetics of clearance of contrast enhancement is an indirect indicator of the survival of encapsulated cells.*Conclusions*The Gd-chitosan probe we developed is promising to follow-up non-invasively the redox microenvironment within cellembedding hydrogels. This approach will find useful application to monitor whether transplanted cells succeed to restore normal tissue oxygenation levels, especially in regenerative medicine approaches to ischemic diseases

Biocompatible Materials labelled with Microenvironment Responsive MRI Probes for the follow-up of Cell Transplants

Introduction: Cell encapsulation by hydrogels is intended to shield transplanted cells from the host hostile environment by preventing the infiltration of host immune cells. Cell scaffolding by solid biocompatible microparticles is intended to provide a structural support to implanted cells and to mimic the extracellular matrix, allowing cells to proliferate and/or differentiate in the desired way. We present strategies to label scaffolding biomaterials with microenvironment responsive MRI probes, for applications in the follow-up of cell transplants. Methods: Microparticles (MPs) based on PLGA/chitosan were incorporated with gadolinium fluoride nanoparticles (GdNPs), as the MRI T1-contrast agent. The system is designed such to release Gd-NPs in the extracellular matrix (ECM), thus activating MRI contrast, unless MPs are attacked by the immune system (Foreign Body Response, FBR). To proof the concept, PLGA-based MPs were seeded with hMSCs and implanted into either immunocompetent or immunocompromised mice, and the transplants were followed-up by MRI for three weeks. Ex-vivo histologic assessment was carried out at the end of the follow-up. Results/Discussion: Immunocompetent mice showed poor activation, if any, of MRI contrast within the cell graft. Immunocompromised mice, on the other hand, showed a progressive activation of MRI contrast. Ex-vivo histology showed extensive FBR directed against microparticles in immunocompetent mice, with some surviving hMSCs in the ECM but not on the scaffold surface. No significant FBR was detected in immunocompromised mice, and hMSCs were still adhering to the scaffolds. Conclusions: The proposed system is able to assess whether or not cell grafts are subjected to innate immune response, an event that is likely correlated to the loss of transplanted cells

Biodegradable microparticles as scaffolds for cell therapy

Cell therapy is promising strategy that has attracted a lot of attention recently regarding regeneration of diverse tissues and treatment of various pathological conditions. Despite its great potential, several issues still need to be addressed. Among them administration route and dose, microenvironment conditions and host immune response are recognized as a major causes which lead to cells transplantation failure. In this work it is presented novel microstructural system based on biodegradable polymer poly(lactide-co-glycolide) (PLGA) and combination of biocompatible polyvinyl alcohol (PVA) and chitosan, as a scaffold for human mesenchymal stem cells (hMSCs) growth. The obtained microparticles with diameter 200-600 μm showed full biocompatibility with human hMSCs. Besides serving as a solid support, polymeric particles provided controlled release of contrast agent - gadolinium fluoride nanoparticles (Gd-NP) up to 5 weeks. The release of Gd-NP is enhanced by acidic conditions. Magnetic Resonance Imaging (MRI) of the samples embedded in 1% agar showed that contrast enhancement in T1-weighted (T1w) MR images is influenced by the amount of released Gd-NP. Based on these preliminary results, presented theranostic system could be considered for cells grafting

Endogenous glutamine decrease is associated with pancreatic cancer progression

Abstract Pancreatic ductal adenocarcinoma (PDAC) is becoming the second leading cause of cancer-related death in the Western world. The mortality is very high, which emphasizes the need to identify biomarkers for early detection. As glutamine metabolism alteration is a feature of PDAC, its in vivo evaluation may provide a useful tool for biomarker identification. Our aim was to identify a handy method to evaluate blood glutamine consumption in mouse models of PDAC. We quantified the in vitro glutamine uptake by Mass Spectrometry (MS) in tumor cell supernatants and showed that it was higher in PDAC compared to non-PDAC tumor and pancreatic control human cells. The increased glutamine uptake was paralleled by higher activity of most glutamine pathway-related enzymes supporting nucleotide and ATP production. Free glutamine blood levels were evaluated in orthotopic and \u202

The Role of Attitudes Toward Medication and Treatment Adherence in the Clinical Response to LAIs: Findings From the STAR Network Depot Study

Background: Long-acting injectable (LAI) antipsychotics are efficacious in managing psychotic symptoms in people affected by severe mental disorders, such as schizophrenia and bipolar disorder. The present study aimed to investigate whether attitude toward treatment and treatment adherence represent predictors of symptoms changes over time. Methods: The STAR Network \u201cDepot Study\u201d was a naturalistic, multicenter, observational, prospective study that enrolled people initiating a LAI without restrictions on diagnosis, clinical severity or setting. Participants from 32 Italian centers were assessed at three time points: baseline, 6-month, and 12-month follow-up. Psychopathological symptoms, attitude toward medication and treatment adherence were measured using the Brief Psychiatric Rating Scale (BPRS), the Drug Attitude Inventory (DAI-10) and the Kemp's 7-point scale, respectively. Linear mixed-effects models were used to evaluate whether attitude toward medication and treatment adherence independently predicted symptoms changes over time. Analyses were conducted on the overall sample and then stratified according to the baseline severity (BPRS < 41 or BPRS 65 41). Results: We included 461 participants of which 276 were males. The majority of participants had received a primary diagnosis of a schizophrenia spectrum disorder (71.80%) and initiated a treatment with a second-generation LAI (69.63%). BPRS, DAI-10, and Kemp's scale scores improved over time. Six linear regressions\u2014conducted considering the outcome and predictors at baseline, 6-month, and 12-month follow-up independently\u2014showed that both DAI-10 and Kemp's scale negatively associated with BPRS scores at the three considered time points. Linear mixed-effects models conducted on the overall sample did not show any significant association between attitude toward medication or treatment adherence and changes in psychiatric symptoms over time. However, after stratification according to baseline severity, we found that both DAI-10 and Kemp's scale negatively predicted changes in BPRS scores at 12-month follow-up regardless of baseline severity. The association at 6-month follow-up was confirmed only in the group with moderate or severe symptoms at baseline. Conclusion: Our findings corroborate the importance of improving the quality of relationship between clinicians and patients. Shared decision making and thorough discussions about benefits and side effects may improve the outcome in patients with severe mental disorders

Clinical features and outcomes of elderly hospitalised patients with chronic obstructive pulmonary disease, heart failure or both

Background and objective: Chronic obstructive pulmonary disease (COPD) and heart failure (HF) mutually increase the risk of being present in the same patient, especially if older. Whether or not this coexistence may be associated with a worse prognosis is debated. Therefore, employing data derived from the REPOSI register, we evaluated the clinical features and outcomes in a population of elderly patients admitted to internal medicine wards and having COPD, HF or COPD + HF. Methods: We measured socio-demographic and anthropometric characteristics, severity and prevalence of comorbidities, clinical and laboratory features during hospitalization, mood disorders, functional independence, drug prescriptions and discharge destination. The primary study outcome was the risk of death. Results: We considered 2,343 elderly hospitalized patients (median age 81 years), of whom 1,154 (49%) had COPD, 813 (35%) HF, and 376 (16%) COPD + HF. Patients with COPD + HF had different characteristics than those with COPD or HF, such as a higher prevalence of previous hospitalizations, comorbidities (especially chronic kidney disease), higher respiratory rate at admission and number of prescribed drugs. Patients with COPD + HF (hazard ratio HR 1.74, 95% confidence intervals CI 1.16-2.61) and patients with dementia (HR 1.75, 95% CI 1.06-2.90) had a higher risk of death at one year. The Kaplan-Meier curves showed a higher mortality risk in the group of patients with COPD + HF for all causes (p = 0.010), respiratory causes (p = 0.006), cardiovascular causes (p = 0.046) and respiratory plus cardiovascular causes (p = 0.009). Conclusion: In this real-life cohort of hospitalized elderly patients, the coexistence of COPD and HF significantly worsened prognosis at one year. This finding may help to better define the care needs of this population

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research