Multifunctional mats by antimicrobial nanoparticles decoration for bioinspired smart wound dressing solutions.

Developing advanced materials for wound dressings is a very challenging, yet unaddressed task. These systems are supposed to act as temporary skin substitutes, performing multiple functions, including fluid absorption and antimicrobial action, supporting cell proliferation and migration in order to promote the skin regeneration process. Following a global bioinspired approach, in this study, we developed a multifunctional textile for wound dressing applications. Biodegradable polyhydroxybutyrate/poly-3-caprolactone (PHB/PCL) mats were fabricated by electrospinning to mimic the extracellular matrix (ECM), thus providing structural and biochemical support to tissue regeneration. Furthermore, inspired by nature's strategy which exploits melanin as an effective weapon against pathogens infection, PHB/PCL mats were modified with hybrid Melanin-TiO2 nanostructures. These were combined to PHB/PCL mats following two different strategies: in-situ incorporation during electrospinning process, alternately ex-post coating by electrospraying onto obtained mats. All samples revealed huge water uptake and poor cytotoxicity towards HaCat eukaryotic cells. Melanin-TiO2 coating conferred PHB/PCL mats significant antimicrobial activity towards both Gram(+) and Gram(-) strains, marked hydrophilic properties as well as bioactivity which is expected to promote materials-cells interaction. This study is going to provide a novel paradigm for the design of active wound dressings for regenerative medicine.

Comparison of cheeses from goats fed 7 forages based on a new health index.

This study proposed the General Health Index of Cheese (GHIC) as an indicator for the presence of health-promoting compounds in cheese and compared the antioxidant capacity and phenolic and fatty acid contents of cheeses from goats consuming 7 forage species. Ninety-one homogeneous Red Syrian goats were randomly assigned to 1 of 7 feeding treatments (Festuca arundinacea, Hordeum vulgare, Triticosecale, Pisum sativum, Trifolium alexandrinum, Vicia sativa, and Vicia faba minor). The housed goat groups received the scheduled forage ad libitum. Forage species affected the antioxidant capacity, the phenolic and fatty acid contents, the Health Promoting Index, and the GHIC. Trifolium alexandrinum, Triticosecale, and Hordeum vulgare showed a clear advantage in terms of beneficial fatty acids content in goat cheese. Cheese from the Triticosecale group also showed a high antioxidant capacity value even if its polyphenol content was intermediate compared with others. Trifolium alexandrinum and Triticosecale had the highest value of the new index GHIC. This comparison suggests that there are important differences in fatty acid profile and polyphenol content among cheeses from goats fed grasses and legumes commonly used in the Mediterranean area. In this first approach, GHIC index, which combines the positive components found in cheese, seems to be a useful tool to provide an indication concerning the general health value of the product.

Imidazoline Receptor Agonists for Managing Hypertension May Hold Promise for Treatment of Intracerebral Hemorrhage.

Intracerebral hemorrhage (ICH), which accounts for 10% of all strokes, leads to higher morbidity and mortality compared with other stroke subtypes. Hypertension has been recognized as a major risk factor for ICH. Current antihypertensive options have not been fully effective for either prevention of ICH or ameliorating its complications. Therefore, attempts should be made to use novel antihypertensive medications for more effective management of blood pressure (BP) in the acute phase of ICH. Imidazoline receptor (IR) agonists can potentially be effective agents for BP control with the adjunctive ability to attenuate post-ICH brain injury. IR agonists render neuroprotective effects including inhibition of inflammatory reactions, apoptotic cell death, excitotoxicity, and brain edema. Given these properties, the present review aims to focus on the application of IR agonists for managing BP in ICH patients.

Trabectedin in Ovarian Cancer: is it now a Standard of Care?

In patients with recurrent ovarian cancer, the choice of second-line therapy is complex. Several factors have to be considered, such as platinum-free interval (PFI), residual toxicity from the previous treatments, BRCA1/2 gene mutation status. Trebectedin is a minor groove DNA binder derived from a marine organism that has shown efficacy in different settings in ovarian cancer therapy. It has been approved in the treatment of partially platinum sensitive (PPS) (PFI between 6 and 12 months) relapsed ovarian cancer according to the statistically significant progression-free survival (7.3 versus 5.8 months) and overall survival (22.2 versus 18.9 months) benefit compared with single-agent pegylated liposomal doxorubicin (PLD) in the OVA 301 phase III trial. This drug has been shown to prolong the time to first subsequent treatment and improve the efficacy of further platinum-based chemotherapy. The role of trabectedin/PLD followed by platinum combination compared with the reverse sequence in PPS is actually in evaluation in the INOVATYON phase III study, which will clarify the best sequence to be adopted in this setting. Trabectedin has been shown to be active in patient carriers of BRCA mutations, probably for its mechanism of action directly affecting DNA and it is actually tested as a single agent in some phase III trials in BRCA mutated and BRCAness ovarian cancer patients. Trabectedin is also active on the immune system. There is, therefore, the rational for new trials of a combination with immune checkpoint inhibitors.

Quality-of-life analysis of the MITO-8, MaNGO, BGOG-Ov1, AGO-Ovar2.16, ENGOT-Ov1, GCIG study comparing platinum-based versus non-platinum-based chemotherapy in patients with partially platinum-sensitive recurrent ovarian cancer.

Background: MITO-8 showed that prolonging platinum-free interval by introducing non-platinum-based chemotherapy (NPBC) does not improve prognosis of patients with partially platinum-sensitive recurrent ovarian cancer. Quality of life (QoL) was a secondary outcome. Patients and methods: Ovarian cancer patients recurring or progressing 6-12 months after previous platinum-based chemotherapy (PBC) were randomized to receive PBC or NPBC as first treatment. QoL was assessed at baseline, third and sixth cycles, with the EORTC C-30 and OV-28 questionnaires. Mean changes and best response were analysed. Progression-free survival, response rate, and toxicity are also reported for proper interpretation of data. All analyses were based on intention-to-treat. Results: Out of the 215 patients, 151 (70.2%) completed baseline questionnaire, balanced between the arms; thereafter, missing rate was higher in the NPBC arm. At mean change analysis, C30 scores were prevalently worse in the NPBC than PBC arm, statistical significance being attained for emotional functioning, global health status/QoL, fatigue, and dyspnoea (effect sizes ranging from 0.30 to 0.51). Conversely, as for OV28 scale, the other chemotherapy side-effects item was significantly worse with PBC at three and six cycles, with a larger effect size (0.70 and 0.54, respectively). At best response analysis, improvement of emotional functioning and pain and worsening of peripheral neuropathy and other chemotherapy side-effects were significantly more frequent in the PBC arm. Progression-free survival (median 9 versus 5 months, P = 0.001) and objective response rate (51.6% versus 19.4%, P = 0.0001) were significantly better with PBC. Allergy, blood cell count, alopecia, nausea, musculoskeletal, and neurological side-effects were more frequent and severe with PBC; hand-foot skin reaction, rash/desquamation, mucositis, and vascular events were more frequent with NPBC. Conclusion: MITO-8 QoL analysis shows that deterioration of some functioning and symptom scales is lower with PBC, with improvement of emotional functioning and pain, despite worsening of toxicity-related items. ClinicalTrials.gov: NCT00657878.

Cisplatin can be safely administered to ovarian cancer patients with hypersensitivity to carboplatin.

OBJECTIVE: Hypersensitivity reactions (HSR) are frequently reported in patients rechallenged with carboplatin for recurrent ovarian cancer (ROC) and represent a critical issue, since discontinuation of the platinum-based therapy could affect prognosis. Several strategies to allow platinum rechallenge have been described, with controversial outcomes. The aim of this study is to illustrate a 10-year experience with cisplatin in patients with a previous HSR to carboplatin or at risk for allergy. METHODS: A retrospective review of all patients with platinum sensitive ROC retreated with carboplatin was performed between January 2007 and May 2016 at the Istituto Nazionale Tumori, Fondazione "G. Pascale", Naples. RESULTS: Among 183 patients, 49 (26.8%) presented HSR to carboplatin, mainly during second line therapy. Mean number of cycles before HSR was 8 (range 3-17). G2, G3 and G4 reaction were detected in 83%, 15% and 2% of patients, respectively. In a multivariate analysis including age, hystotype, BRCA status, previous known HSR, and combination drug administered, only the type of carboplatin-based doublet used as 2nd line therapy was found to significantly affect HSR development, with a protective effect of PLD (pegylated liposomal doxorubicin) (p = 0.014, OR = 0.027). Thirty seven patients (77%) with a previous HSR to carboplatin were rechallenged with cisplatin. Treatment was generally well tolerated. 5 patients (13.1%) experienced mild HSR to cisplatin, successfully managed in all cases. 14 patients were treated with cisplatin even without a carboplatin-related HSR due to other allergies. Among these, only one developed HSR (7.1%). CONCLUSIONS: Cisplatin rechallenge is a feasible approach in patients experiencing HSR to carboplatin to maintain the beneficial effect of platinum while reducing hypersensitivity-related risks.

Prospective phase II trial of trabectedin in BRCA-mutated and/or BRCAness phenotype recurrent ovarian cancer patients: the MITO 15 trial.

BACKGROUND: Current evidence suggest that trabectedin is particularly effective in cells lacking functional homologous recombination repair mechanisms. A prospective phase II trial was designed to evaluate the activity of trabectedin in the treatment of recurrent ovarian cancer patients presenting BRCA mutation and/or BRCAness phenotype. PATIENTS AND METHODS: A total of 100 patients with recurrent BRCA-mutated ovarian cancer and/or BRCAness phenotype (≥2 previous responses to platinum) were treated with trabectedin 1.3 mg/mq i.v. q 3 weeks. The activity of the drug with respect to BRCA mutational status and to a series of polymorphisms [single-nucleotide polymorphisms (SNPs)] involved in DNA gene repair was analyzed. RESULTS: Ninety-four were evaluable for response; in the whole population, 4 complete and 33 partial responses were registered for an overall response rate (ORR) of 39.4. In the platinum-resistant (PR) and -sensitive (PS) population, an ORR of 31.2% and 47.8%, and an overall clinical benefit of 54.2% and 73.9%, respectively, were registered. In the whole series, the median progression-free survival (PFS) was 18 weeks and the median overall survival (OS) was 72 weeks; PS patients showed a more favorable PFS and OS compared with PR patients. BRCA gene mutational status was available in 69 patients. There was no difference in ORR, PFS and OS according to BRCA 1-2 status nor any association between SNPs of genes involved in DNA repair and NER machinery and response to trabectedin was reported. CONCLUSIONS: Our data prospectively confirmed that the signature of 'repeated platinum sensitivity' identifies patients highly responsive to trabectedin. In this setting, the activity of trabectedin seems comparable to what could be obtained using platinum compounds and the drug may represent a valuable alternative option in patients who present contraindication to receive platinum. EUDRACT NUMBER: 2011-001298-17.

Monomeric C-reactive protein--a key molecule driving development of Alzheimer's disease associated with brain ischaemia?

Alzheimer's disease (AD) increases dramatically in patients with ischaemic stroke. Monomeric C-reactive protein (mCRP) appears in the ECM of ischaemic tissue after stroke, associating with microvasculature, neurons and AD-plaques, Aß, also, being able to dissociate native-CRP into inflammatory, mCRP in vivo. Here, mCRP injected into the hippocampal region of mice was retained within the retrosplenial tract of the dorsal 3rd ventrical and surrounding major vessels. Mice developed behavioural/cognitive deficits within 1 month, concomitant with mCRP staining within abnormal looking neurons expressing p-tau and in beta-amyloid 1-42-plaque positive regions. mCRP co-localised with CD105 in microvessels suggesting angiogenesis. Phospho-arrays/Western blotting identified signalling activation in endothelial cells and neurons through p-IRS-1, p-Tau and p-ERK1/2-which was blocked following pre-incubation with mCRP-antibody. mCRP increased vascular monolayer permeability and gap junctions, increased NCAM expression and produced haemorrhagic angiogenesis in mouse matrigel implants. mCRP induced tau244-372 aggregation and assembly in vitro. IHC study of human AD/stroke patients revealed co-localization of mCRP with Aß plaques, tau-like fibrils and IRS-1/P-Tau positive neurons and high mCRP-levels spreading from infarcted core regions matched reduced expression of Aß/Tau. mCRP may be responsible for promoting dementia after ischaemia and mCRP clearance could inform therapeutic avenues to reduce the risk of future dementia.

Intravesical chemo-immunotherapy in non muscle invasive bladder cancer.

Non-Muscle-Invasive-Bladder-Cancer represents 75-85% of the new bladder cancer cases per year. Trans-uretral vesical resection is the milestone for diagnosis and therapy. After primary treatment, recurrence is frequent depending on the presence of several established risk factors: multiplicity, T dimension, prior recurrence. In some patients disease progress to an advanced stage. Adjuvant chemo-immunotherapy has been widely used depending on the risk category assigned on the basis of the risk factors for recurrence. In low risk categories a one shot treatment with chemotherapy is considered the standard treatment without any maintenance therapy. In intermediate risk patients, adjuvant induction therapy and maintenance chemotherapy or immunotherapy for at least one year is recommended. In high risk patients adjuvant induction and maintenance immunotherapy until 3 years is considered the best strategy. In this review data on the different drugs used in this setting will be discussed.

Multidisciplinary treatment of early stage endometrial cancer.

Endometrial cancer is a highly curable malignancy when it presents as uterine-confined disease, but the prognosis for metastatic or recurrent endometrial cancer is poor. For those patients which are diagnosed at an early stage, surgery alone may be adequate for cure and clinical outcome is often favorable, with approximately 80 % of cases surviving at 5 years. However, after primary diagnosis and treatment, roughly 20-30% of patients are expected to recur within the following 5 years. Adjuvant treatment for endometrial cancer is not yet clearly defined. FIGO Stage I-III endometrial cancer patients, usually undergo surgery and some of them are offered adjuvant treatment based on risk assessment. Grade, age, stage are considered all independent risk factors for recurrence. Radiotherapy (RT) has been considered the adjuvant treatment of choice for decades, being able to reduce local recurrence rate and improving progression free survival, but without any impact on overall survival. In the last two decades, a shift toward the use of systemic chemotherapy (CT) in addition or instead of radiation has occurred, although few prospective studies have been performed in this field.

C-reactive protein in ischemic stroke: an independent prognostic factor.

BACKGROUND AND PURPOSE: There is growing evidence of the prognostic importance of C-reactive protein (CRP) in ischemic stroke. However, the independent value of CRP at different stages after stroke has not been established. Therefore, we assessed the prognostic values of CRP in ischemic stroke. We also compared the relation of CRP at admission and discharge with 1-year outcome. METHODS: One hundred ninety-three patients were included in a derivation set (n=128) and a validation set (n=65). Serum CRP was measured, within 24 hours after index ischemic stroke, within 48 to 72 hours, and at hospital discharge. We examined the association between the level of CRP at different stages after stroke and outcome. We adjusted for the possible confounding effect using a multivariate Cox proportional hazard model. RESULTS: A cutoff point of 1.5 mg/dL for CRP at discharge provided optimum sensitivity and specificity for adverse outcome, based on the receiver operator curves. CRP at admission (hazard ratio [HR] 2.78, 95% CI 1.45 to 5.33; P=0.0021) and discharge (HR 9.42, 95% CI 4.27 to 19.05; P<0.0001) were predictors of the combined end point of new vascular events or death at 1 year. CRP at hospital discharge was the strongest independent marker of adverse outcome (HR 7.42, 95% CI 2.75 to 20.03; P=0.0001). These results were confirmed in the validation set (HR 15.66, 95% CI 3.36 to 72.97; P=0.0005). CONCLUSIONS: CRP is a marker of increased 1-year risk in ischemic stroke. CRP at discharge is better related to later outcome and could be of greater utility for risk stratification. These findings are consistent with the hypothesis that elevated CRP may predict future cardiovascular events or death.

Prognostic influence of increased C-reactive protein and fibrinogen levels in ischemic stroke.

BACKGROUND AND PURPOSE: The prognostic influences of fibrinogen and C-reactive protein (CRP) levels and their relations in ischemic stroke have not been well described. The aim of this study was to investigate and compare the 1-year prognostic influences of fibrinogen and CRP levels on outcome in ischemic stroke. METHODS: Fibrinogen and CRP were determined within 24 hours after stroke and related to 1-year outcome in 128 patients with first-ever ischemic stroke. The Kaplan-Meier technique was applied in survival analysis. Multiple logistic regression analysis was used to evaluate the associations between risk factors and outcome. RESULTS: The probabilities of death or new vascular event were 21.1%, 27.9%, and 51.7% (P:=0.0172, chi(2) for trend), respectively, in patients stratified by tertiles of fibrinogen (<3.78, 3.78 to 6.17, and >6.17 g/L). The probabilities of a primary end point were 12.1%, 29.7%, and 54.8% (P:=0.0004), respectively, after stratification of patient data by tertiles of CRP level (<5, 5 to 33, and >33 mg/L). In multiple logistic regression analysis, higher CRP levels (odds ratio, 2.39; 95% CI, 1.28 to 4.49; P:=0.0066) and stroke severity on the Canadian Neurological Stroke Scale (odds ratio, 2.37; 95% CI, 1.01 to 5.58; P:=0.0472) were independently associated with death or new vascular event. CONCLUSIONS: Increased levels of CRP are associated with a worse outcome in patients with ischemic stroke. The increased risk associated with elevated CRP levels is independent of the prognostic influence of fibrinogen.