Exploring the Impact of Hepatic Impairment on Pralsetinib Pharmacokinetics.

Pralsetinib is a kinase inhibitor indicated for the treatment of metastatic rearranged during transfection (RET) fusion-positive non-small cell lung cancer. Pralsetinib is primarily eliminated by the liver and hence hepatic impairment (HI) is likely alter its pharmacokinetics (PK). Mild HI has been shown to have minimal impact on the PK of pralsetinib. This hepatic impairment study aimed to determine the pralsetinib PK, safety and tolerability in subjects with moderate and severe HI, as defined by the Child-Pugh and National Cancer Institute Organ Dysfunction Working Group (NCI-ODWG) classification systems, in comparison to subjects with normal hepatic function. Based on the Child-Pugh classification, subjects with moderate and severe HI had similar systemic exposure (area under the plasma concentration time curve from time 0 to infinity [AUC0-∞]) to pralsetinib, with AUC0-∞ geometric mean ratios (GMR) of 1.12 and 0.858, respectively, compared to subjects with normal hepatic function. Results based on the NCI-ODWG classification criteria were comparable; the AUC0-∞ GMR were 1.22 and 0.858, respectively, for subjects with moderate and severe HI per NCI-ODWG versus those with normal hepatic function. These results suggested that moderate and severe hepatic impairment did not have a meaningful impact on the exposure to pralsetinib, thus not warranting a dose adjustment in this population.

Pralsetinib in Patients with Advanced/Metastatic Rearranged During Transfection (RET)-Altered Thyroid Cancer: Updated Efficacy and Safety Data from the ARROW Study.

Background: Rearranged during transfection (RET) alterations are targetable oncogenic drivers in thyroid cancer. Primary data from the open-label, phase 1/2 ARROW study demonstrated clinical activity and manageable safety with pralsetinib, a selective RET inhibitor, in patients with advanced/metastatic RET-altered thyroid cancer. We present an updated analysis with more patients and longer follow-up. Methods: Adult patients with advanced/metastatic RET-mutant medullary thyroid cancer (MTC) or RET fusion-positive thyroid cancer who initiated oral pralsetinib at 400 mg once daily were included. Primary endpoints were overall response rate (ORR) by blinded independent central review (per RECIST v1.1) and safety. Secondary endpoints included duration of response (DoR), progression-free survival (PFS), and overall survival. Responses were assessed in three cohorts of patients with baseline measurable disease: patients with RET-mutant MTC who had received prior cabozantinib and/or vandetanib (C/V), treatment-naïve patients with RET-mutant MTC, and patients with previously treated RET fusion-positive thyroid cancer. Patient-reported outcomes (PROs) were an exploratory endpoint. Results: As of October 18, 2021, the measurable disease population comprised of 61 patients with RET-mutant MTC and prior C/V, 62 treatment-naïve patients with RET-mutant MTC, and 22 patients with RET fusion-positive thyroid cancer who had received prior systemic therapy, including radioactive iodine. The ORR was 55.7% [confidence interval; 95% CI: 42.4-68.5] in patients with RET-mutant MTC and prior C/V, 77.4% [95% CI: 65.0-87.1] in treatment-naïve patients with RET-mutant MTC, and 90.9% [95% CI: 70.8-98.9] in patients with previously treated RET fusion-positive thyroid cancer. Median DoR and median PFS were both 25.8 months in patients with RET-mutant MTC and prior C/V, not reached in treatment-naïve patients with RET-mutant MTC, and 23.6 and 25.4 months, respectively, in patients with previously treated RET fusion-positive thyroid cancer. In the RET-altered thyroid cancer safety population (N = 175), 97.1% of patients reported a treatment-related adverse event (TRAE); these led to discontinuation in 5.7% and dose reduction in 52.6% of patients. There was one death (0.6%) due to a TRAE. PROs improved or remained stable after pralsetinib treatment. Conclusions: In this updated analysis of the ARROW study, pralsetinib continued to show deep and durable clinical activity and a manageable safety profile in patients with advanced/metastatic RET-altered thyroid cancer. Clinical Trial Registration: NCT03037385.

Updating datasets of ionospheric parameters provided by SCINDA GNSS receiver from Lisbon airport area with full data sets for 2014-2019.

An updated dataset based on data from a GNSS receiver with the SCINDA software installed in Lisbon airport area are presented: the new dataset cover the entire time interval from December 2014 to February 2019, except for the original SCINDA data for 2015, which can be found in the original version of the paper. The dataset consists of 2 parts: (1) data produced by SCINDA; (2) processed data. The types of the data produced by SCINDA are described in the original paper. The processed data are the TEC, S4, ROTI and position (latitude, longitude, altitude) extracted from the SCINDA data. Since the receiver was not calibrated when installed a provisionally calibrated TEC data is provided. The processing of the original SCINDA data was done using (1) a dedicated "SCINDA-Iono" toolbox for MATLAB; (2) scripts for R. Both the MATLAB toolbox and the R scripts allow to calculate 1-min and 1-hour means for ionospheric parameters both for each of available receiver-satellite pairs and averaged over all available satellites during the analysed hour, however the toolbox and the scripts are not interchangeable.

Elucidation of critical pH-dependent structural changes in Botulinum Neurotoxin E.

Botulinum Neurotoxins (BoNT) are the most potent toxins currently known. However, they also have therapeutic applications for an increasing number of motor related conditions due to their specificity, and low diffusion into the system. Although the start- and end- points for the BoNT mechanism of action are well-studied, a critical step remains poorly understood. It is theorised that BoNTs undergo a pH-triggered conformational shift, activating the neurotoxin by priming it to form a transmembrane (TM) channel. To test this hypothesis, we combined molecular dynamics (MD) simulations and small-angle x-ray scattering (SAXS), revealing a new conformation of serotype E (BoNT/E). This conformation was exclusively observed in simulations below pH 5.5, as determined by principal component analysis (PCA), and its theoretical SAXS profile matched an experimental SAXS profile obtained at pH 4. Additionally, a localised secondary structural change was observed in MD simulations below pH 5.5, in a region previously identified as instrumental for membrane insertion for serotype A (BoNT/A). These changes were found at a critical pH value for BoNTs in vivo, and may be relevant for their therapeutic use.

Factors that Influence Treatment Delay for Patients with Breast Cancer.

INTRODUCTION: The diagnosis or treatment of breast cancer is sometimes delayed. A lengthy delay may have a negative psychological impact on patients. The aim of our study was to evaluate the sociodemographic, clinical and pathological factors associated with delay in the provision of surgical treatment for localised breast cancer, in a prospective cohort of patients. METHODS: This observational, prospective, multicentre study was conducted in ten hospitals belonging to the Spanish national public health system, located in four Autonomous Communities (regions). The study included 1236 patients, diagnosed through a screening programme or found to be symptomatic, between April 2013 and May 2015. The study variables analysed included each patient's personal history, care situation, tumour history and data on the surgical intervention, pathological anatomy, hospital admission and follow-up. Treatment delay was defined as more than 30 days elapsed between biopsy and surgery. RESULTS: Over half of the study population experienced surgical treatment delay. This delay was greater for patients with no formal education and among widows, persons not requiring assistance for usual activities, those experiencing anxiety or depression, those who had a high BMI or an above-average number of comorbidities, those who were symptomatic, who did not receive NMR spectroscopy, who presented a histology other than infiltrating ductal carcinoma or who had poorly differentiated carcinomas. CONCLUSIONS: Certain sociodemographic and clinical variables are associated with surgical treatment delay. This study identifies factors that influence surgical delays, highlighting the importance of preventing these factors and of raising awareness among the population at risk and among health personnel.

Datasets of ionospheric parameters provided by SCINDA GNSS receiver from Lisbon airport area.

Here we present datasets provided by a SCINDA GNSS receiver installed in the Lisbon airport area from November of 2014 to July of 2019. The installed equipment is a NovAtel EURO4 with a JAVAD Choke-Ring antenna. The data are in an archived format and include the general messages on quality of records (*.msg), RANGE files (*.rng), raw observables as the signal-to-noise (S/N) ratios, pseudoranges and phases (*.obs), receiver position information (*.psn), ionosphere scintillations monitor (ISMRB; *.ism) and ionospheric parameters: total electron content (TEC), rate of change of TEC index (ROTI), and the scintillation index S4 (*.scn). The presented data cover the full 2015 year. The raw data are of 1-min resolution and available for each of the receiver-satellite pairs. The processing and the analysis of the ionosphere scintillation datasets can be done using a specific "SCINDA-Iono" toolbox for the MATLAB developed by T. Barlyaeva in 2019 and available online via MathWorks File Exchange system. The toolbox calculates 1-h means for ionospheric parameters for each of the available receiver-satellite pairs and averaged over all available satellites during the analyzed hour. Here we present the processed data for the following months in 2015: March, June, October, and December. The months were selected as containing most significant geomagnetic events of 2015. The 1-h means for other months can be obtained from the raw data using the aforementioned toolbox. The provided datasets are interesting for the GNSS and ionosphere based scientific communities.

An update on the use of molecular modeling in dendrimers design for biomedical applications: are we using its full potential?

INTRODUCTION: Dendrimers are well-defined hyperbranched polymers built from a variety of different monomers and with tuneable properties that make them suitable for different biomedical applications. Their three-dimensional (3D) structure cannot be usually determined experimentally due to their inherent nature of repeating patterns in the topology, failure to crystalize, and/or high flexibility. Therefore, their conformations and interactions at the atomistic level can be studied only by using computational chemistry methods, including molecular dynamics, Monte Carlo simulations, and molecular docking. AREAS COVERED: In this review, the methods that could be utilized in computer-aided dendrimer design are considered, providing a list of approaches to generate initial 3D coordinates and selected examples of applications of relevant molecular modeling methods. EXPERT OPINION: Computational chemistry provides an invaluable set of tools to study dendrimers and their interactions with drugs and biological targets. There is a gap in the software development that is dedicated to study of these highly variable and complex systems that could be overcome by the integration of already established approaches for topology generation and open source molecular modeling libraries. Furthermore, it would be highly beneficial to collate already built 3D models of various dendrimers with corresponding relevant experimental data.

Factors associated with readmissions in women participating in screening programs and treated for breast cancer: a retrospective cohort study.

BACKGROUND: We aimed to identify the risk factors associated with early, late and long-term readmissions in women diagnosed with breast cancer participating in screening programs. METHODS: We performed a multicenter cohort study of 1055 women aged 50-69 years participating in Spanish screening programs, diagnosed with breast cancer between 2000 and 2009, and followed up to 2014. Readmission was defined as a hospital admission related to the disease and/or treatment complications, and was classified as early (< 30 days), late (30 days-1 year), or long-term readmission (> 1 year). We used logistic regression to estimate the adjusted odds ratios (aOR), and 95% confidence intervals (95% CI) to explore the factors associated with early, late and long-term readmissions, adjusting by women's and tumor characteristics, detection mode, treatments received, and surgical and medical complications. RESULTS: Among the women included, early readmission occurred in 76 (7.2%), late readmission in 87 (8.2%), long-term readmission in 71 (6.7%), and no readmission in 821 (77.8%). Surgical complications were associated with an increased risk of early readmissions (aOR = 3.62; 95%CI: 1.27-10.29), and medical complications with late readmissions (aOR = 8.72; 95%CI: 2.83-26.86) and long-term readmissions (aOR = 4.79; 95%CI: 1.41-16.31). CONCLUSION: Our results suggest that the presence of surgical or medical complications increases readmission risk, taking into account the detection mode and treatments received. Identifying early complications related to an increased risk of readmission could be useful to adapt the management of patients and reduce further readmissions. TRIAL REGISTRATION: ClinicalTrials.govIdentifier: NCT03165006. Registration date: May 22, 2017 (Retrospectively registered).

Exploring the Role of Breast Density on Cancer Prognosis among Women Attending Population-Based Screening Programmes.

BACKGROUND: Our aim was to assess the role of breast density on breast cancer mortality and recurrences, considering patient and tumour characteristics and the treatments received among women attending population-based screening programmes. METHODS: We conducted a retrospective cohort study among women aged 50-69 years attending population-based screening programmes, diagnosed with invasive breast cancer between 2000 and 2009, and followed up to 2014. Breast density was categorised as low density (≤25% dense tissue), intermediate density (25-50%), and high density (≥50%). Cox proportional hazards regression models were fitted to estimate the adjusted hazard ratios (aHR) and 95% confidence intervals (95% CI) for death and recurrences, adjusting by patient characteristics, mode of detection (screen-detected vs. interval cancer), and tumour features. RESULTS: The percentage of deaths and recurrences was higher among women with intermediate- and high-density breasts than among women with low-density breasts (p=0.011 for death; p=0.037 for recurrences). Adjusted Cox proportional hazards regression models revealed that women with intermediate- and high-density breasts had a higher risk of death than women with low-density breasts, being statistically significant for intermediate densities (aHR = 2.19 [95% CI: 1.16-4.13], aHR = 1.44 [95% CI: 0.67-3.1], respectively). No association was found between breast density and recurrences. CONCLUSIONS: Breast density was associated with a higher risk of death, but not of recurrences, among women participating in breast cancer screening. These findings reinforce the need to improve screening sensitivity among women with dense breasts and to routinely assess breast density, not only for its role as a risk factor for breast cancer but also for its potential influence on cancer prognosis.

Variabilidad en la práctica de la cirugía mamaria en mujeres participantes en el programa de cribado poblacional de cáncer de mama / Variability of breast surgery in women participating in breast cancer screening programs

Introducción: Actualmente la variabilidad en la práctica quirúrgica constituye un problema a resolver. El objetivo de nuestro estudio es describir la variabilidad en la realización del tratamiento quirúrgico del cáncer de mama y analizar los factores asociados a la misma. Métodos: La población de estudio comprende 1.057 mujeres diagnosticadas de cáncer de mama y tratadas quirúrgicamente procedentes de la cohorte retrospectiva CaMISS. Resultados: La edad media en el momento del diagnóstico fue de 59,3 ± 5 años. Se diagnosticaron 732 pacientes mediante mamografías de cribado y 325 pacientes como cánceres de intervalo. La realización de mastectomía fue más frecuente en los tumores detectados entre intervalos (OR = 2,5; [IC 95%: 1,8-3,4]), aunque este efecto desaparece al ajustar por el resto de variables. El factor más determinante asociado a la realización de una mastectomía fue el TNM: los tumores con estadio iii-iv presentaron una OR de 7,4 (IC 95%: 3,9-13,8), aumentando en la OR ajustada hasta 21,7 (IC 95%: 11,4-41,8). Histológicamente el carcinoma lobulillar infiltrante mantiene la significación en la OR ajustada (Ora = 2,5; [IC 95%: 1,4-4,7]). Según el programa de cribado existen diferencias significativas en el tratamiento quirúrgico. El programa 3 presenta una ORa de cirugía tipo mastectomía de 4 [IC 95%: 1,8-8,9]. Este programa coincide con el de mayor porcentaje de reconstrucción (58,3%). Conclusiones: Este estudio muestra cómo a pesar de tener en cuenta las características de las pacientes y del tumor, existe una elevada variabilidad en el tipo de cirugía en función del lugar de diagnóstico

Introduction: Currently, variability in surgical practice is a problem to be solved. The aim of this study is to describe the variability in the surgical treatment of breast cancer and to analyze the factors associated with it. Methods: The study population included 1057 women diagnosed with breast cancer and surgically treated. Our data were from the CaMISS retrospective cohort. Results: The mean age at diagnosis was 59.3 ± 5 years. A total of 732 patients were diagnosed through screening mammograms and 325 patients as interval cancers. The mastectomy surgery was more frequent in the tumors detected between intervals (OR = 2.5; [95%CI: 1.8-3.4]), although this effect disappeared when we adjusted for the rest of the variables. The most important factor associated with performing a mastectomy was TNM: tumors in stage III-IV had an OR of 7.4 [95%CI: 3.9-13.8], increasing in adjusted OR to 21.7 [95%CI: 11.4-41.8]. Histologically, infiltrating lobular carcinoma maintains significance in adjusted OR (OR = 2.5; [95%CI: 1.4-4.7]). According to the screening program, there were significant differences in surgical treatment. Program 3 presented an OR of non-conservative surgery of 4.0 [95%CI: 1.8-8.9]. This program coincided with the highest percentage of reconstruction (58.3%). Conclusions: This study shows that, despite taking into account patient and tumor characteristics, there is great variability in the type of surgery depending on the place of diagnosis

Variability of breast surgery in women participating in breast cancer screening programs. / Variabilidad en la práctica de la cirugía mamaria en mujeres participantes en el programa de cribado poblacional de cáncer de mama.

INTRODUCTION: Currently, variability in surgical practice is a problem to be solved. The aim of this study is to describe the variability in the surgical treatment of breast cancer and to analyze the factors associated with it. METHODS: The study population included 1057 women diagnosed with breast cancer and surgically treated. Our data were from the CaMISS retrospective cohort. RESULTS: The mean age at diagnosis was 59.3 ± 5 years. A total of 732 patients were diagnosed through screening mammograms and 325 patients as interval cancers. The mastectomy surgery was more frequent in the tumors detected between intervals (OR=2.5; [95%CI: 1.8-3.4]), although this effect disappeared when we adjusted for the rest of the variables. The most important factor associated with performing a mastectomy was TNM: tumors in stage III-IV had an OR of 7.4 [95%CI: 3.9-13.8], increasing in adjusted OR to 21.7 [95%CI: 11.4-41.8]. Histologically, infiltrating lobular carcinoma maintains significance in adjusted OR (OR=2.5; [95%CI: 1.4-4.7]). According to the screening program, there were significant differences in surgical treatment. Program 3 presented an OR of non-conservative surgery of 4.0 [95%CI: 1.8-8.9]. This program coincided with the highest percentage of reconstruction (58.3%). CONCLUSIONS: This study shows that, despite taking into account patient and tumor characteristics, there is great variability in the type of surgery depending on the place of diagnosis.

Survival and Disease-Free Survival by Breast Density and Phenotype in Interval Breast Cancers.

Background: We aimed to evaluate survival and disease-free survival in different subtypes of interval cancers by breast density, taking into account clinical and biological characteristics.Methods: We included 374 invasive breast tumors (195 screen-detected cancers; 179 interval cancers, classified into true interval, false-negatives, occult tumors and minimal-sign cancers) diagnosed in women ages 50-69 years undergoing biennial screening from 2000-2009, followed up to 2014. Breast density was categorized into non-dense (<25% dense tissue) and mixed dense breasts (≥25%). Survival curves were generated by the Kaplan-Meier method and compared by the log-rank test. Cox proportional hazard regression models were computed to estimate the adjusted hazard ratios (aHRs) and 95% confidence intervals (95% CIs) for death and recurrences by comparing women with interval and true interval cancers versus women with screen-detected cancers, controlling for tumor and patient characteristics. All analyses were stratified by breast density.Results: Interval cancers were detected in younger women, at more advanced stages, in denser breasts and showed a higher proportion of triple-negative cancers, especially among true interval cancers. Women with interval cancer and non-dense breasts had an aHR for death of 3.40 (95% CI, 0.92-12.62). Women with true interval cancers detected in non-dense breasts had the highest adjusted risk of death (aHR, 6.55; 95% CI, 1.37-31.39).Conclusions: Women with true interval cancer in non-dense breasts had a higher risk of death than women with screen-detected cancers.Impact: These results support the advisability of routinely collecting information on breast density, both for further tailoring of screening strategies and as a prognostic factor for diagnosed breast cancers. Cancer Epidemiol Biomarkers Prev; 27(8); 908-16. ©2018 AACR.

α-Galactosylceramide and peptide-based nano-vaccine synergistically induced a strong tumor suppressive effect in melanoma.

α-Galactosylceramide (GalCer) is a glycolipid widely known as an activator of Natural killer T (NKT) cells, constituting a promising adjuvant against cancer, including melanoma. However, limited clinical outcomes have been obtained so far. This study evaluated the synergy between GalCer and major histocompatibility complex (MHC) class I and MHC class II melanoma-associated peptide antigens and the Toll-Like Receptor (TLR) ligands CpG and monophosphoryl lipid A (MPLA), which we intended to maximize following their co-delivery by a nanoparticle (NP). This is expected to improve GalCer capture by dendritic cells (DCs) and subsequent presentation to NKT cells, simultaneously inducing an anti-tumor specific T-cell mediated immunity. The combination of GalCer with melanoma peptides and TLR ligands successfully restrained tumor growth. The tumor volume in these animals was 5-fold lower than the ones presented by mice immunized with NPs not containing GalCer. However, tumor growth was controlled at similar levels by GalCer entrapped or in its soluble form, when mixed with antigens and TLR ligands. Those two groups showed an improved infiltration of T lymphocytes into the tumor, but only GalCer-loaded nano-vaccine induced a prominent and enhanced infiltration of NKT and NK cells. In addition, splenocytes of these animals secreted levels of IFN-γ and IL-4 at least 1.5-fold and 2-fold higher, respectively, than those treated with the mixture of antigens and adjuvants in solution. Overall, the combined delivery of the NKT agonist with TLR ligands and melanoma antigens via this multivalent nano-vaccine displayed a synergistic anti-tumor immune-mediated efficacy in B16F10 melanoma mouse model. STATEMENT OF SIGNIFICANCE: Combination of α-galactosylceramide (GalCer), a Natural Killer T (NKT) cell agonist, with melanoma-associated antigens presented by MHC class I (Melan-A:26) and MHC class II (gp100:44) molecules, and Toll-like Receptor (TLR) ligands (MPLA and CpG), within nanoparticle matrix induced a prominent anti-tumor immune response able to restrict melanoma growth. An enhanced infiltration of NKT and NK cells into tumor site was only achieved when the combination GalCer, antigens and TLR ligands were co-delivered by the nanovaccine.

Rational design of novel, fluorescent, tagged glutamic acid dendrimers with different terminal groups and in silico analysis of their properties.

Dendrimers are hyperbranched polymers with a multifunctional architecture that can be tailored for the use in various biomedical applications. Peptide dendrimers are particularly relevant for drug delivery applications due to their versatility and safety profile. The overall lack of knowledge of their three-dimensional structure, conformational behavior and structure-activity relationship has slowed down their development. Fluorophores are often conjugated to dendrimers to study their interaction with biomolecules and provide information about their mechanism of action at the molecular level. However, these probes can change dendrimer surface properties and have a direct impact on their interactions with biomolecules and with lipid membranes. In this study, we have used computer-aided molecular design and molecular dynamics simulations to identify optimal topology of a poly(l-glutamic acid) (PG) backbone dendrimer that allows incorporation of fluorophores in the core with minimal availability for undesired interactions. Extensive all-atom molecular dynamic simulations with the CHARMM force field were carried out for different generations of PG dendrimers with the core modified with a fluorophore (nitrobenzoxadiazole and Oregon Green 488) and various surface groups (glutamic acid, lysine and tryptophan). Analysis of structural and topological features of all designed dendrimers provided information about their size, shape, internal distribution and dynamic behavior. We have found that four generations of a PG dendrimer are needed to ensure minimal exposure of a core-conjugated fluorophore to external environment and absence of undesired interactions regardless of the surface terminal groups. Our findings suggest that NBD-PG-G4 can provide a suitable scaffold to be used for biophysical studies of surface-modified dendrimers to provide a deeper understanding of their intermolecular interactions, mechanisms of action and trafficking in a biological system.

Practical computational toolkits for dendrimers and dendrons structure design.

Dendrimers and dendrons offer an excellent platform for developing novel drug delivery systems and medicines. The rational design and further development of these repetitively branched systems are restricted by difficulties in scalable synthesis and structural determination, which can be overcome by judicious use of molecular modelling and molecular simulations. A major difficulty to utilise in silico studies to design dendrimers lies in the laborious generation of their structures. Current modelling tools utilise automated assembly of simpler dendrimers or the inefficient manual assembly of monomer precursors to generate more complicated dendrimer structures. Herein we describe two novel graphical user interface toolkits written in Python that provide an improved degree of automation for rapid assembly of dendrimers and generation of their 2D and 3D structures. Our first toolkit uses the RDkit library, SMILES nomenclature of monomers and SMARTS reaction nomenclature to generate SMILES and mol files of dendrimers without 3D coordinates. These files are used for simple graphical representations and storing their structures in databases. The second toolkit assembles complex topology dendrimers from monomers to construct 3D dendrimer structures to be used as starting points for simulation using existing and widely available software and force fields. Both tools were validated for ease-of-use to prototype dendrimer structure and the second toolkit was especially relevant for dendrimers of high complexity and size.

Systematic review and network meta-analysis of tedizolid for the treatment of acute bacterial skin and skin structure infections caused by MRSA.

BACKGROUND: Tedizolid, the active moiety of tedizolid phosphate, is approved in the United States, the European Union, Canada and a number of other countries for the treatment of acute bacterial skin and skin structure infections (ABSSSI) caused by certain susceptible bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). This network meta-analysis (NMA) evaluates the comparative effectiveness of tedizolid and other antibacterials indicated for the treatment of ABSSSI caused by MRSA. METHODS: Systematic review of 10 databases was undertaken to inform an NMA to estimate the relative effectiveness of tedizolid and established monotherapy comparators (ceftaroline, daptomycin, linezolid, teicoplanin, tigecycline, vancomycin) for treating MRSA-associated ABSSSI. Randomized controlled trials enrolling adults with ABSSSI or complicated skin and skin structure infections caused by suspected/documented MRSA were eligible for inclusion. Networks were developed based on similarity of study design, patient characteristics, outcome measures and available data. Outcomes of interest included clinical response at end of therapy (EOT), post-therapy evaluation (PTE) or test-of-cure assessment and treatment discontinuations resulting from adverse events (AEs). Bayesian NMA was conducted for each outcome using fixed-effects and random effects models. RESULTS: Literature searches identified 3,618 records; 15 trials met the inclusion criteria and were considered suitable for NMA comparison. In fixed-effects models, tedizolid had higher odds of clinical response at EOT (odds ratio [OR], 1.7; credible interval, 1.0, 3.0) and PTE than vancomycin (OR, 1.6; credible interval, 1.1, 2.5). No differences in odds of clinical response at EOT or PTE were observed between tedizolid and other comparators. There was no evidence of a difference among treatments for discontinuation due to AEs. Results from random effects and fixed-effects models were generally consistent. CONCLUSIONS: Tedizolid was superior to vancomycin for clinical response at EOT and PTE. There was no evidence of a difference between tedizolid and other comparators and no evidence of a difference between tedizolid and all comparators when evaluating discontinuation due to AEs. These findings suggest that tedizolid provides an alternative option for the management of serious skin infections caused by suspected or documented MRSA. This study is subject to the limitations inherent in all NMAs, and the results should be interpreted accordingly.

Prevalence of persistent pain after breast cancer treatment by detection mode among participants in population-based screening programs.

BACKGROUND: To date, the study of the risks and benefits of breast cancer screening has not included the onset of persistent pain after breast cancer treatment within the context of population-based screening programs. Our purpose was to investigate the prevalence of persistent pain and associated factors in women diagnosed with breast cancer (screening or interval) in the context of a population-based breast cancer screening program in Spain. METHODS: A total of 1,057 women participating in a population-based breast cancer screening program were diagnosed with breast cancer between 2000 and 2008. The women were treated surgically and followed-up to 2013. The risk of developing persistent pain was estimated through multivariate logistic regression analysis. RESULTS: Breast cancer was detected during routine screening in 732 women (69.3 %) and emerged as an interval cancer between two screening rounds in 325 (30.7 %). Persistent pain was present in 118 women (11.3 %). Women diagnosed through routine screening reported a higher prevalence of persistent pain (12.9 %) than those with interval cancers (7.8 %)(P < 0.05). Multivariate logistic regression analysis identified two other variables associated with persistent pain: having a Charlson index > =2 (Odds Ratio [OR]: 4.5 95 % Confidence Interval [CI]: 2.1-9.5) versus no comorbidities, and having undergone an axillary lymph node dissection (OR: 2.0 95 % CI: 1.0-4.0) versus sentinel lymph node biopsy. CONCLUSIONS: The prevalence of persistent pain was relatively low. The detection mode was not related to the onset of persistent pain. The factors associated with persistent pain were a Charlson index > =2 and the performance of axillary lymph node dissection. Women treated for breast cancer are at risk for developing persistent pain regardless of the detection mode, especially those with comorbidities and those who have undergone axillary lymph node dissection.

Identification of Protein-Excipient Interaction Hotspots Using Computational Approaches.

Protein formulation development relies on the selection of excipients that inhibit protein-protein interactions preventing aggregation. Empirical strategies involve screening many excipient and buffer combinations using force degradation studies. Such methods do not readily provide information on intermolecular interactions responsible for the protective effects of excipients. This study describes a molecular docking approach to screen and rank interactions allowing for the identification of protein-excipient hotspots to aid in the selection of excipients to be experimentally screened. Previously published work with Drosophila Su(dx) was used to develop and validate the computational methodology, which was then used to determine the formulation hotspots for Fab A33. Commonly used excipients were examined and compared to the regions in Fab A33 prone to protein-protein interactions that could lead to aggregation. This approach could provide information on a molecular level about the protective interactions of excipients in protein formulations to aid the more rational development of future formulations.

Mammographic and clinical characteristics of different phenotypes of screen-detected and interval breast cancers in a nationwide screening program.

In the context of a population-based screening program, we aimed to evaluate the major mammographic features and clinicopathological characteristics of breast tumors at diagnosis and the associations between them, focusing on tumors with the worst prognosis. We analyzed cancers diagnosed in a cohort of 645,764 women aged 45-69 years participating in seven population-based screening programs in Spain, between January 1, 2000 and December 31, 2006 and followed up until June 2009. We included all interval cancers and a sample of screen-detected cancers, whether invasive or in situ. We compared tumor-related information and breast density for different phenotypes (Triple-negative (TN), HER2+, Luminal B and Luminal A) in screen-detected and interval cancers. We used Chi-square or Fisher's exact test to compare major mammographic features of invasive versus in situ tumors, of screen-detected versus interval cancers, and of different types of interval cancers. We included 2582 tumors (1570 screen-detected and 1012 interval cancers). There were significant differences in the distribution of most clinicopathological variables between screen-detected and interval cancers. Invasive TN interval tumors were more common than other phenotypes in breasts with low mammographic density; three-quarters of these tumors presented as masses without associated calcifications. HER2+ tumors were more common in denser breasts and were associated with calcifications and multifocality. Architectural distortion was more common in Luminal A and Luminal B tumors. Certain radiologic findings are associated with pre-invasive lesions; these differ among invasive tumor phenotypes. We corroborate that TN and HER2+ cancers have distinctive appearances also in the context of population-based screening programs. This information can be useful for establishing protocols for diagnostic strategies in screening units.

Cancer immunotherapy: nanodelivery approaches for immune cell targeting and tracking.

Cancer is one of the most common diseases afflicting people globally. New therapeutic approaches are needed due to the complexity of cancer as a disease. Many current treatments are very toxic and have modest efficacy at best. Increased understanding of tumor biology and immunology has allowed the development of specific immunotherapies with minimal toxicity. It is important to highlight the performance of monoclonal antibodies, immune adjuvants, vaccines and cell-based treatments. Although these approaches have shown varying degrees of clinical efficacy, they illustrate the potential to develop new strategies. Targeted immunotherapy is being explored to overcome the heterogeneity of malignant cells and the immune suppression induced by both the tumor and its microenvironment. Nanodelivery strategies seek to minimize systemic exposure to target therapy to malignant tissue and cells. Intracellular penetration has been examined through the use of functionalized particulates. These nano-particulate associated medicines are being developed for use in imaging, diagnostics and cancer targeting. Although nano-particulates are inherently complex medicines, the ability to confer, at least in principle, different types of functionality allows for the plausible consideration these nanodelivery strategies can be exploited for use as combination medicines. The development of targeted nanodelivery systems in which therapeutic and imaging agents are merged into a single platform is an attractive strategy. Currently, several nanoplatform-based formulations, such as polymeric nanoparticles, micelles, liposomes and dendrimers are in preclinical and clinical stages of development. Herein, nanodelivery strategies presently investigated for cancer immunotherapy, cancer targeting mechanisms and nanocarrier functionalization methods will be described. We also intend to discuss the emerging nano-based approaches suitable to be used as imaging techniques and as cancer treatment options.