Spectroscopic analysis of the binding of paraquat and diquat herbicides to biosubstrates

The study of the interaction of persistent organic pollutants with biosubstrates helps to unravel the pathways for toxicity, however, few mechanistic data are present in the literature for these systems. We analyzed the binding of paraquat (PQ) and diquat (DQ) herbicides to natural calf thymus DNA and a DNA G-quadruplex by spectrophotometric titrations, ethidium bromide exchange tests, viscometry, and melting experiments. The interaction with bovine serum albumin (BSA) protein was studied spectrofluorimetrically at different temperatures. The retention of the targets on positive, negative, and neutral micellar aggregates and liposomes was analyzed by ultrafiltration experiments. Despite some favorable features, PQ and DQ only externally bind natural DNA and do not interact with DNA oligonucleotides. Both herbicides bind bovine serum albumin (BSA). PQ binds BSA mainly according to an electrostatics-driven process. However, ultrafiltration data also show that some hydrophobic contribution participates in the features of these systems. The practical problems related to unfavorable spectroscopic signals and inner filter effects are also discussed. Overall, both herbicides show a low affinity for nucleic acids and weak penetration into liposomes; in addition, the equilibrium constants values found for BSA system suggest optimal conditions for transport in the body

Prospective study on nanoparticle albumin-bound paclitaxel in advanced breast cancer. Clinical results and biological observations in taxane-pretreated patients

Background: There is a deep need to improve the care of metastatic breast cancer (MBC) patients, since even today it remains an incurable disease. Taxanes are considered the most effective cytotoxic drugs for the treatment of MBC, both in monotherapy and in combined schedules, but the need for synthetic solvents contributes to the severe toxicities and may have a negative impact on the efficacy. Nanoparticle albumin-bound paclitaxel (Nab-paclitaxel) is a colloidal suspension of paclitaxel and human serum albumin initially developed to avoid the toxicities associated with conventional taxanes. Patients and methods: The aim of this prospective, single-center open-label, noncomparative study was to evaluate the efficacy and safety of nab-paclitaxel in MBC patients pretreated with taxanes. The patients were treated with nab-paclitaxel as a single agent, 260 mg/m2 on day 1 of each 3-week cycle or 125 mg/m2 weekly. The primary endpoint was the overall response rate (ORR). Secondary objectives were duration of response, clinical benefit rate, progression-free survival (PFS), overall survival, and safety. Results: A total of 42 patients (median age 48 years, median Eastern Cooperative Oncology Group performance status 0, triple-negative MBC 19%, all pretreated with a taxane-based therapy, mainly in advanced disease) were enrolled in the study. The ORR was 23.8%, including one complete response (2.4%) and nine partial responses (21.4%); the disease control rate was 50%. The median duration of response was 7.2 months. After a median follow-up of 9 months, the median PFS was 4.6 months. ORR and PFS were similar irrespective of the previous chemotherapy lines, metastatic sites, and biomolecular expression. Nab-paclitaxel was well tolerated, and the most frequent treatment-related toxicities were mild to moderate (grades 1–2). Conclusion: This real-life study shows that nab-paclitaxel has a significant antitumor activity and a manageable safety profile in patients pretreated with taxanes and experiencing a treatment failure after at least one line of chemotherapy

Molecular analysis of sarcomeric and non-sarcomeric genes in patients with hypertrophic cardiomyopathy.

Background: Hypertrophic cardiomyopathy (HCM) is a common genetic heart disorder characterized by unexplained left ventricle hypertrophy associated with non-dilated ventricular chambers. Several genes encoding heart sarcomeric proteins have been associated to HCM, but a small proportion of HCM patients harbor alterations in other non-sarcomeric loci. The variable expression of HCM seems influenced by genetic modifier factors and new sequencing technologies are redefining the understanding of genotype–phenotype relationships, even if the interpretations of the numerous identified variants pose several challenges. Methods and results: We investigated 62 sarcomeric and non-sarcomeric genes in 41 HCM cases and in 3 HCM-related disorders patients. We employed an integrated approach that combines multiple tools for the prediction, annotation and visualization of functional variants. Genotype–phenotype correlations were carried out for inspecting the involvement of each gene in age onset and clinical variability of HCM. The 80% of the non-syndromic patients showed at least one rare non-synonymous variant (nsSNV) and among them, 58% carried alterations in sarcomeric loci, 14% in desmosomal and 7% in other non-sarcomeric ones without any sarcomere change. Statistical analyses revealed an inverse correlation between the number of nsSNVs and age at onset, and a relationship between the clinical variability and number and type of variants. Conclusions: Our results extend the mutational spectrum of HCM and contribute in defining the molecular pathogenesis and inheritance pattern(s) of this condition. Besides, we delineate a specific procedure for the identification of the most likely pathogenetic variants for a next generation sequencing approach embodied in a clinical context

Green-synthetized silver nanoparticles for Nanoparticle-Enhanced Laser Induced Breakdown Spectroscopy (NELIBS) using a mobile instrument

When compared to other analytical techniques, LIBS shows relatively low precision and, generally, high Limits of Detection (LODs). Until recently, the attempts in improving the LIBS performances have been based on the use of more stable/powerful lasers, high sensitivity detectors or controlled environmental parameters. This can hinder the competitiveness of LIBS by increasing the instrumental setup cost and the difficulty of operation. Sample treatment has proved to be a viable and simple way to increase the LIBS signal; in particular, the Nanoparticle-Enhanced Laser Induced Breakdown Spectroscopy (NELIBS) methodology uses a deposition of metal nanoparticles on the sample to greatly increase the emission of the LIBS plasma. In this work, we used a simple, fast, â\u80\u9cgreenâ\u80\u9d and low-cost method to synthetize silver nanoparticles by using coffee extract as reducing agents for a silver nitrate solution. This allowed us to obtain nanoparticles of about 25 nm in diameter. We then explored the application of such nanoparticles to the NELIBS analysis of metallic samples with a mobile LIBS instrument. By adjusting the laser parameters and optimizing the sample preparation procedure, we obtained a NELIBS signal that is 4 times the LIBS one. This showed the potential of green-synthetized nanoparticle for NELIBS applications and suggests the possibility of an in-situ application of the technique

Acute myocardial infarction following off label retrobulbar injection of desmopressin for non-arteritic anterior ischemic optic neuropathy (NAION). Causal correlation or coincidence?

A 60-year-old man, apparently healthy with negative history for cardiovascular diseases, was hospitalized because of an unilateral sudden and painless severe visual loss. Diagnosis of NAION was made. Two separate and immediately consecutive injections of betamethasone (2 mg/0.5 mL) and desmopressin (2 mcg/0.5 mL) were performed in the retrobulbar space. Fifteen minutes later, the patient suddenly developed cold sweat, dyspnoea, thoracic pain and severe hypotension. Acute myocardial infarction was diagnosed by ECG. Desmopressin was the probable causative agent. Thrombotic events following intravenous or oral administration of desmopressin have been documented in the medical literature. To the best of our knowledge this is the first case in which a thrombotic event was associated with the retrobulbar route. Retrobulbar desmopressin administration in patients with NAION can be probably associated with AMI. Considering its invasiveness and the unproven benefit in the treatment of NAION, this therapeutic approach can not be currently recommende

Real-world efficacy and safety of nivolumab in previously-treated metastatic renal cell carcinoma, and association between immune-related adverse events and survival: the Italian expanded access program

Background: The Italian Renal Cell Cancer Early Access Program was an expanded access program that allowed access to nivolumab, for patients (pts) with metastatic renal cell carcinoma (mRCC) prior to regulatory approval. Methods: Pts with previously treated advanced or mRCC were eligible to receive nivolumab 3 mg/kg every 2 weeks. Pts included in the analysis had received ≥1 dose of nivolumab and were monitored for drug-related adverse events (drAEs) using CTCAE v.4.0. Immune-related (ir) AEs were defined as AEs displaying a certain, likely or possible correlation with immunotherapy (cutaneous, endocrine, hepatic, gastro-intestinal and pulmonary). The association between overall survival (OS) and irAEs was assessed, and associations between variables were evaluated with a logistic regression model. Results: A total of 389 pts were enrolled between July 2015 and April 2016. Overall, the objective response rate was 23.1%. At a median follow-up of 12 months, the median progression-free survival was 4.5 months (95% CI 3.7-6.2) and the 12-month overall survival rate was 63%. Any grade and grade 3-4 drAEs were reported in 124 (32%) and 27 (7%) of pts, respectively, and there were no treatment-related deaths. Any grade irAEs occurred in 76 (20%) of patients, 8% cutaneous, 4% endocrine, 2% hepatic, 5% gastro-intestinal and 1% pulmonary. Of the 22 drAEs inducing treatment discontinuation, 10 (45%) were irAEs. Pts with drAEs had a significantly longer survival than those without drAEs (median OS 22.5 versus 16.4 months, p = 0.01). Pts with irAEs versus without irAEs had a more significant survival benefit (median OS not reached versus 16.8 months, p = 0.002), confirmed at the landmark analysis at 6 weeks. The occurrence of irAEs displayed a strong association with OS in univariable (HR 0.48, p = 0.003) and multivariable (HR 0.57, p = 0.02) analysis. Conclusions: The appearance of irAEs strongly correlates with survival benefit in a real-life population of mRCC pts treated with nivolumab

A phase Ib study combining the second-generation DNA hypomethylating agent (DHA) guadecitabine (SGI-110) and ipilimumab in patients with metastatic melanoma: The NIBIT-M4 Study

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External validation on a prospective basis of a nomogram for predicting the time to first treatment in patients with chronic lymphocytic leukemia

BACKGROUND: A nomogram that incorporates traditional and newer prognostic factors to identify patients with chronic lymphocytic leukemia (CLL) who are at high risk of receiving therapy was developed by investigators at The University of Texas M. D. Anderson Cancer Center (MDACC). Because the model required validation before its extensive use could be recommended, the authors sought to externally validate the nomogram in an independent, community-based cohort of patients with CLL. METHODS: In total, 328 previously untreated patients with newly diagnosed, asymptomatic, Binet stage A CLL from different primary hematology centers who were registered on a prospective basis during 2006 to 2010 on an observational database of the Italian Lymphoma Study Group were considered suitable for external validation of the model. RESULTS: A total point score was calculated for each patient using a formula proposed by MDACC investigators, and the median score was 19.9 (range, 0-69.5). Furthermore, when the score was evaluated as continuous variable (ie, by measuring the risk of each point increase), the total point score was associated with the time to first treatment (hazard ratio [HR], 1.04; 95% confidence interval [CI], 1.02-1.05; P < .0001). Receiver operating characteristic analysis identified a point score of 25 (area under curve; 0.64; sensitivity, 61.5; specificity, 72.1; P < .0001) as the best threshold capable of separating patients who needed therapy from patients who did not (HR, 3.27; 95% CI, 2,07-5.18; P < .0001). The prognostic index category also remained a predictor of the time to first treatment when the analysis was limited to patients with Rai stage 0 disease (HR, 4.05; 95% CI, 2.25-7.52; P < .0001). Finally, a goodness-of-fit test demonstrated that the nomogram model had a significantly good fit at 2 years (correlation coefficient [r2] = 0.966; P = .002). CONCLUSIONS: The current results confirmed the ability of a newly developed prognostic index to predict the time to first treatment among previously untreated patients with CLL who had early disease and extended the utility of the model to those with Rai stage 0 disease. In addition, the actual and predicted time to first treatment outcomes revealed good agreement, suggesting that, externally, the results provided by the model are well calibrated. Cancer 2013. © 2012 American Cancer Society