Drug combination and repurposing for cancer therapy: the example of breast cancer

Cancer is a set of extremely complex diseases, which are increasingly prominent today, as it affects and kills millions of people worldwide, being the subject of intense study both in its pathophysiology and therapy. Especially in women, breast cancer is still a cancer with a high incidence and mortality. Even though mortality rates for this type of cancer have declined in recent years, it remains challenging at the treatment level, especially the metastatic type. Due to all the impact on health, cancer therapy is the subject of costly and intense research. To enrich this therapy, as well as decrease its underlying high associated costs, drug repurposing and drug combinations are strategies that have been increasingly studied and addressed. As the name implies, drug repurposing presupposes giving new purposes to agents which, in this case, are approved for the therapy of other diseases (for example, cardiovascular or metabolic diseases), but are not approved for cancer therapy. Therefore, a better knowledge of these therapeutic modalities for breast cancer therapy is crucial for improved therapy. In this particular review, we will discuss some relevant aspects of cancer and, particularly, breast cancer and its therapy. Also, drug combination and repurposing will be highlighted, together with relevant examples. Despite some limitations that need to be overcome, these methodologies are extremely important and advantageous in combating several current problems of cancer therapy, namely in terms of costs and resistance to current therapeutic modalities. These approaches will be explored with a special focus on breast cancer.This work was supported by FEDER - Fundo Europeu de Desenvolvimento Regional funds through the COMPETE 2020 - Operational Programme for Competitiveness and Internationalisation (POCI), Portugal 2020, and by Portuguese funds through FCT - Fundação para a Ciência e a Tecnologia , in the framework of the projects supported by National Funds through FCT, within CINTESIS, R&D Unit (reference UIDB/4255/2020). N. Vale was supported by FCT and FEDER (European Union), award number IF/00092/2014/CP1255/CT0004

Urethrocystography: a guide for urological surgery?

Urethrocystography remains the gold-standard technique for urethral pathology diagnosis. Nowadays, of the various indications for performing urethrocystography, the most common is due to a clinical suspicion of urethral stricture. Due to the high prevalence of strictures and their substantial impact on a patient's quality of life, the examination must allow the location, exclusion of multifocality, and assessment of the extent of the stricture to influence surgical planning. This article intends to demonstrate that the radiologist's role, by performing and interpreting the modality of urethrocystography, influences and is crucial for the urologic therapeutic decision and that the patients who were submitted to reconstruction by urethroplasty had a better success rate. The authors aim to review the radiological anatomy of the male urethra, discuss the modalities of choice for imaging the urethra (retrograde urethrography and voiding cystourethrography), provide an overview of the different indications for performing the study, examine the different etiologies for urethral strictures, understand the relevance of the different appearances of urethral pathology, and identify the surgical options, especially in the treatment of urethral strictures. Simultaneously, the study exposes cases of urethral trauma, fistulas, diverticulum, and congenital abnormalities.info:eu-repo/semantics/publishedVersio

Ambulatory chest physiotherapy in mild-to-moderate acute bronchiolitis in children under two years of age - A randomized control trial

Objective: The aim of this study was to compare the role of a chest physiotherapy (CP) intervention to no intervention on the respiratory status of children under two years of age, with mild-to-moderate bronchiolitis. Methods: Out of 80 eligible children observed in the Emergency Room, 45 children completed the study with 28 randomized to the intervention group and 17 to the control group. The intervention protocol, applied in an ambulatory setting, consisted of combined techniques of passive prolonged slow expiration, rhinopharyngeal clearance and provoked cough. The control group was assessed with no chest physiotherapy intervention. The efficacy of chest physiotherapy was assessed using the Kristjansson Respiratory Score at the admission and discharge of the visit to the Emergency Room and during clinical visits at day 7 and day 15. Results: There was a significant improvement in the Kristjansson Respiratory Score in the intervention group compared to the control group at day 15 [1.2 (1.5) versus 0.3 (0.5); p -value =0.005 , in the control and intervention groups, respectively], with a mean difference (95% CI) of −0.9 ( −1.6 to −0.3 ). Conclusion: Chest physiotherapy had a positive impact on the respiratory status of children with mild-to-moderate bronchiolitis. Clinical trial registration: https://clinicaltrials.gov/ct2/show/NCT04260919

is there a link?

PMID:25076895Spinal cord infarction (SCI) is an uncommon but important cause of acute myelopathy. Nevertheless, contrary to cerebral stroke, the discussion about paradoxical embolism as a cause of cryptogenic SCI remains dubious. We describe the case of a 24-year-old woman who developed sudden-onset back pain followed by upper limb paralysis. T2-weighted MRI demonstrated hyperintense signal, extending from C5 to D1 with corresponding restricted diffusion on diffusion-weighted MRI and reduction of the apparent diffusion coefficient. Diagnostic workup, including lumbar puncture, showed no changes. Transcranial Doppler showed a right-to-left shunt with an uncountable number of microembolic signals after Valsalva maneuvers, and a patent foramen ovale (PFO) with an atrial septum aneurysm was identified. We discuss the paucity of evidence of right-to-left shunting in spinal diseases compared to cerebral events and the potential role of paradoxical embolism through PFO as a possible mechanism of SCI.publishersversionpublishe

REALMS Study: Real-World Effectiveness and Safety of Fingolimod in Patients with Relapsing-Remitting Multiple Sclerosis in Portugal

Background: Fingolimod, an oral sphingosine 1-phosphate receptor modulator, is approved by EMA for relapsing-remitting multiple sclerosis (RRMS). Objectives: To assess the effectiveness and safety of fingolimod in patients with RRMS in real-world clinical practice in Portugal. Methods: Retrospective, multicentre, non-interventional study, reporting 3 years follow-up of data collected from October 2015 to July 2016. Sociodemographic data and previous treatments at baseline and data regarding disease evolution, including number of relapses, annualised relapse rates (ARR) and Expanded Disability Status Scale (EDSS), were collected. Results: Two-hundred and seventy-five participants were enrolled in the REALMS study. Results showed that the main reason to switch to fingolimod was failure of previous treatment (56.7%) and only 3.6% were naïve patients. In the total population, there was a significant decrease in ARR of 64.6% in the first year of treatment, 79.7% in the second year and 82.3% in the third year, compared with baseline. More than 67.0% of patients had no relapses during the 3 years after switching to fingolimod. EDSS remained stable throughout the study. Conclusions: Therapy with fingolimod showed a sustained effectiveness and safety over the 3 years, particularly on patients switched from first-line drugs (BRACE). No new safety issues were reported.info:eu-repo/semantics/publishedVersio

Arsenite oxidase in complex with antimonite and arsenite oxyanions - insights into the catalytic mechanism

Arsenic contamination of groundwater is among one of the biggest health threats affecting millions of people in the world. There is an urgent need for efficient arsenic biosensors where the use of arsenic metabolizing enzymes can be explored. In this work we have solved the crystal structures of four complexes of arsenite oxidase (Aio) obtained in complex with arsenic and antimony oxyanions and the structures determined correspond to intermediate states of the enzymatic mechanism. These structural data were complemented with DFT calculations providing a unique view of the molybdenum active site at different time points that, together with mutagenesis data, enabled to clarify the enzymatic mechanism and the molecular determinants for the oxidation of As(III) to the less toxic As(V) species

Target-Oriented Synthesis of Marine Coelenterazine Derivatives with Anticancer Activity by Applying the Heavy-Atom Effect

Photodynamic therapy (PDT) is an anticancer therapeutic modality with remarkable advantages over more conventional approaches. However, PDT is greatly limited by its dependence on external light sources. Given this, PDT would benefit from new systems capable of a light-free and intracellular photodynamic effect. Herein, we evaluated the heavy-atom effect as a strategy to provide anticancer activity to derivatives of coelenterazine, a chemiluminescent single-molecule widespread in marine organisms. Our results indicate that the use of the heavy-atom effect allows these molecules to generate readily available triplet states in a chemiluminescent reaction triggered by a cancer marker. Cytotoxicity assays in different cancer cell lines showed a heavy-atom-dependent anticancer activity, which increased in the substituent order of hydroxyl < chlorine < bromine. Furthermore, it was found that the magnitude of this anticancer activity is also dependent on the tumor type, being more relevant toward breast and prostate cancer. The compounds also showed moderate activity toward neuroblastoma, while showing limited activity toward colon cancer. In conclusion, the present results indicate that the application of the heavy-atom effect to marine coelenterazine could be a promising approach for the future development of new and optimized self-activating and tumor-selective sensitizers for light-free PDT

In vitro and in vivo performance of methacrylated gellan gum hydrogel formulations for cartilage repair

Methacrylated gellan gum (GGMA) formulation is proposed as a second‐generation hydrogel for controlled delivery of cartilage‐forming cells into focal chondral lesions, allowing immediate in situ retention of cells and 3D filling of lesion volume, such approach deemed compatible with an arthroscopic procedure. Formulation optimization was carried out in vitro using chondrocytes and adipose mesenchymal stromal/stem cells (ASCs). A proof‐of‐concept in vivo study was conducted using a rabbit model with induced chondral lesions. Outcomes were compared with microfracture or non‐treated control. Three grading scores were used to evaluate tissue repair after 8 weeks by macroscopic, histological and immunohistochemical analysis. Intense collagen type II and low collagen type I gene and protein expression were achieved in vitro by the ASC + GGMA formulation, in light with development of healthy chondral tissue. In vivo, this formulation promoted significantly superior de novo cartilage formation compared with the non‐treated group. Maintenance of chondral height and integration with native tissue was further accomplished. The physicochemical properties of the proposed GGMA hydrogel exhibited highly favorable characteristics and biological performance both in vitro and in vivo, positioning itself as an attractive xeno‐free biomaterial to be used with chondrogenic cells for a cost‐effective treatment of focal chondral lesions

Tailored biocompatible polyurethane-poly(ethylene glycol) hydrogels as a versatile nonfouling biomaterial

Polyurethane-based hydrogels are relatively inexpensive and mechanically robust biomaterials with ideal properties for various applications, including drug delivery, prosthetics, implant coatings, soft robotics, and tissue engineering. In this report, a simple method is presented for synthesizing and casting biocompatible polyurethane-poly(ethylene glycol) (PU-PEG) hydrogels with tunable mechanical properties, nonfouling characteristics, and sustained tolerability as an implantable material or coating. The hydrogels are synthesized via a simple one-pot method using commercially available precursors and low toxicity solvents and reagents, yielding a consistent and biocompatible gel platform primed for long-term biomaterial applications. The mechanical and physical properties of the gels are easily controlled by varying the curing concentration, producing networks with complex shear moduli of 0.82–190 kPa, similar to a range of human soft tissues. When evaluated against a mechanically matched poly(dimethylsiloxane) (PDMS) formulation, the PU-PEG hydrogels demonstrated favorable nonfouling characteristics, including comparable adsorption of plasma proteins (albumin and fibrinogen) and significantly reduced cellular adhesion. Moreover, preliminary murine implant studies reveal a mild foreign body response after 41 days. Due to the tunable mechanical properties, excellent biocompatibility, and sustained in vivo tolerability of these hydrogels, it is proposed that this method offers a simplified platform for fabricating soft PU-based biomaterials for a variety of applications

A Multicenter, Non-Interventional Study to Evaluate the Disease Activity in Multiple Sclerosis after Withdrawal of Natalizumab in Portugal

Objectives: Natalizumab (NTZ) is very effective for treatment of relapsing-remitting multiple sclerosis (RRMS), its use is mainly limited by safety issues. Discontinuation of NTZ is associated with recurrence of disease activity (reactivation and rebound). The best strategy for subsequent therapy and the predictive factors for recurrence in such patients are areas of active research. We aimed to evaluate predictors of reactivation in a multicentric study. Patients and methods: Multicentric retrospective observational study in five portuguese MS referral centers. Demographic, clinical and imagiological data were collected in the year prior, during and in the year following NTZ discontinuation. Predictors of reactivation and rebound after NTZ suspension were studied using a multivariate Cox model. Results: Sixty-nine patients were included. They were mainly non-naïve patients (97%), with a mean age of 29.1 ± 8.3 years at diagnosis, and a mean age of 37.2 ± 10.3 years at NTZ initiation. The mean annualized relapse rate (ARR) previous, during and after NTZ was 1.6 ± 1.2, 0.2 ± 0.5 and 0.6 ± 1.0, respectively. The median EDSS before, during and after NTZ was 3.5 (IQR 3.3), 3.5 (IQR 3.5) and 4.0 (IQR 3.8), respectively. The median number of infusions was 26.0 (IQR 12.5) and the main reason to NTZ discontinuation was progressive multifocal leukoencephalopathy (PML) risk (70%). After NTZ suspension, reactivation was observed in 25 (36%) patients after a median time of 20.0 (IQR 29.0) weeks. Reactivation predictors in our sample included NTZ suspension for reasons other than PML (adjusted HR = 0.228, 95% CI [0.084- 0.616], p = 0.004), ARR before NTZ (adjusted HR = 1.914 95% [CI 1.330-2.754], p < 0.001) and a longer disease duration at time of NTZ initiation (adjusted HR = 1.154, 95% CI [1.020-1.306], p = 0.023). Rebound occurred in 5 (7%) patients after a median time of 20 (IQR 34.5) weeks. Conclusion: Significant predictors of disease reactivation in our cohort were discontinuation of NTZ for reasons other than PML risk, higher disease activity before NTZ treatment, and longer disease duration. Our study provides valuable data of portuguese patients after NTZ withdrawal.info:eu-repo/semantics/publishedVersio