Patient's self-reported quality of life as a prognostic factor in metastatic renal cell carcinoma initially treated with TKI: nomogram proposal.

BACKGROUND: Numerous prognostic factors have been described for metastatic renal cell carcinoma (mRCC). There are nomograms to assist in clinical decision-making and inform patients of their disease progression. However, they have a limited capacity and moderate concordance rates. Performance status (PS) is one of the most widely used prognostic factors and most closely related to overall survival (OS), but this is a subjective assessment based solely on the clinician's opinion. Patients must be at the center of care. Patient-reported outcomes (PROs) have shown benefits but are not widespread in daily clinical practice. METHODS: We analyzed 78 consecutive patients diagnosed with mRCC who initiated treatment at our institution between September 2012 and September 2019. We performed a descriptive analysis of the sample's baseline characteristics and the NCCN FKSI 19 questionnaire. We also conducted a survival analysis. RESULTS: The baseline FKSI 19 score demonstrates its prognostic potential, HR of 0.94 (95% CI 0.92-0.97). Our prognostic model would include: FKSI < 58 (HR 3.61 95% CI 1.97-6.61), anemia, thrombocytosis, non-clear cell histology, and metastatic hepatic involvement. AUC 0.86 (95%CI 0.77-0.95). CONCLUSION: Although it would need external validation, the proposed nomogram could be an alternative to other previously described models. The NCCN FKSI 19 baseline score could replace the clinician's subjective determination of PS. CLINICAL TRIAL REGISTRATION: Not applicable.

N-aryltetrahydroisoquinoline derivatives as HA-CD44 interaction inhibitors: Design, synthesis, computational studies, and antitumor effect.

Hyaluronic acid (HA) plays a crucial role in tumor growth and invasion through its interaction with cluster of differentiation 44 (CD44), a non-kinase transmembrane glycoprotein, among other hyaladherins. CD44 expression is elevated in many solid tumors, and its interaction with HA is associated with cancer and angiogenesis. Despite efforts to inhibit HA-CD44 interaction, there has been limited progress in the development of small molecule inhibitors. As a contribution to this endeavour, we designed and synthesized a series of N-aryltetrahydroisoquinoline derivatives based on existing crystallographic data available for CD44 and HA. Hit 2e was identified within these structures for its antiproliferative effect against two CD44+ cancer cell lines, and two new analogs (5 and 6) were then synthesized and evaluated as CD44-HA inhibitors by applying computational and cell-based CD44 binding studies. Compound 2-(3,4,5-trimethoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-5-ol (5) has an EC50 value of 0.59 µM against MDA-MB-231 cells and is effective to disrupt the integrity of cancer spheroids and reduce the viability of MDA-MB-231 cells in a dose-dependent manner. These results suggest lead 5 as a promising candidate for further investigation in cancer treatment.

Response Surface Methodology for the Optimization of Flavan-3-ols Extraction from Avocado By-Products via Sonotrode Ultrasound-Assisted Extraction.

Avocado peel and seed are the main by-products of avocado processing and are considered as promising sources of phenolic compounds with biological activities. Thus, this research focuses on the establishment, for the first time, of ultrasound-assisted extraction of flavan-3-ols with high antioxidant activity from avocado peel and seed using a sonotrode. Indeed, 2 Box-Behnken designs were performed for 15 experiments, with each design having three independent factors (ratio ethanol/water (v/v), time (min) and amplitude (%)). In both models, the responses included total procyanidins (flavan-3-ols) measured via HPLC-FLD and antioxidant activity measured via DPPH, ABTS and FRAP. The results showed that applying the sonotrode extraction method could increase flavan-3-ols recovery by 54% and antioxidant activity by 62-76% compared to ultrasound bath technology. Therefore, this technology was demonstrated to be a non-thermal, low time-consuming and scalable method that allowed the recovery of flavan-3-ols from avocado by-products that could be used as functional ingredients.

Strategies to Re-Sensitize Castration-Resistant Prostate Cancer to Antiandrogen Therapy.

Since prostate cancer (PCa) was described as androgen-dependent, the androgen receptor (AR) has become the mainstay of its systemic treatment: androgen deprivation therapy (ADT). Although, through recent years, more potent drugs have been incorporated, this chronic AR signaling inhibition inevitably led the tumor to an incurable phase of castration resistance. However, in the castration-resistant status, PCa cells remain highly dependent on the AR signaling axis, and proof of it is that many men with castration-resistant prostate cancer (CRPC) still respond to newer-generation AR signaling inhibitors (ARSis). Nevertheless, this response is limited in time, and soon, the tumor develops adaptive mechanisms that make it again nonresponsive to these treatments. For this reason, researchers are focused on searching for new alternatives to control these nonresponsive tumors, such as: (1) drugs with a different mechanism of action, (2) combination therapies to boost synergies, and (3) agents or strategies to resensitize tumors to previously addressed targets. Taking advantage of the wide variety of mechanisms that promote persistent or reactivated AR signaling in CRPC, many drugs explore this last interesting behavior. In this article, we will review those strategies and drugs that are able to resensitize cancer cells to previously used treatments through the use of "hinge" treatments with the objective of obtaining an oncological benefit. Some examples are: bipolar androgen therapy (BAT) and drugs such as indomethacin, niclosamide, lapatinib, panobinostat, clomipramine, metformin, and antisense oligonucleotides. All of them have shown, in addition to an inhibitory effect on PCa, the rewarding ability to overcome acquired resistance to antiandrogenic agents in CRPC, resensitizing the tumor cells to previously used ARSis.

In Cellulo Bioorthogonal Catalysis by Encapsulated AuPd Nanoalloys: Overcoming Intracellular Deactivation.

Bioorthogonal metallocatalysis has opened up a xenobiotic route to perform nonenzymatic catalytic transformations in living settings. Despite their promising features, most metals are deactivated inside cells by a myriad of reactive biomolecules, including biogenic thiols, thereby limiting the catalytic functioning of these abiotic reagents. Here we report the development of cytocompatible alloyed AuPd nanoparticles with the capacity to elicit bioorthogonal depropargylations with high efficiency in biological media. We also show that the intracellular catalytic performance of these nanoalloys is significantly enhanced by protecting them following two different encapsulation methods. Encapsulation in mesoporous silica nanorods resulted in augmented catalyst reactivity, whereas the use of a biodegradable PLGA matrix increased nanoalloy delivery across the cell membrane. The functional potential of encapsulated AuPd was demonstrated by releasing the potent chemotherapy drug paclitaxel inside cancer cells. Nanoalloy encapsulation provides a novel methodology to develop nanoreactors capable of mediating new-to-life reactions in cells.

New amidine-benzenesulfonamides as iNOS inhibitors for the therapy of the triple negative breast cancer.

Triple negative breast cancer (TNBC) is a specific breast cancer subtype, and poor prognosis is associated to this tumour when it is in the metastatic form. The overexpression of the inducible Nitric Oxide Synthase (iNOS) is considered a predictor of poor outcome in TNBC patients, and this enzyme is reported as a valuable molecular target to compromise TNBC progression. In this work, new amidines containing a benzenesulfonamide group were designed and synthesized as selective iNOS inhibitors. An in vitro biological evaluation was performed to assess compounds activity against both the inducible and constitutive NOSs. The most interesting compounds 1b and 2b were evaluated on MDA-MB-231 cells as antiproliferative agents, and 1b capability to counteract cell migration was also studied. Finally, an in-depth docking study was performed to shed light on the observed potency and selectivity of action of the most promising compounds.

Selective Anticancer Therapy Based on a HA-CD44 Interaction Inhibitor Loaded on Polymeric Nanoparticles.

Hyaluronic acid (HA), through its interactions with the cluster of differentiation 44 (CD44), acts as a potent modulator of the tumor microenvironment, creating a wide range of extracellular stimuli for tumor growth, angiogenesis, invasion, and metastasis. An innovative antitumor treatment strategy based on the development of a nanodevice for selective release of an inhibitor of the HA-CD44 interaction is presented. Computational analysis was performed to evaluate the interaction of the designed tetrahydroisoquinoline-ketone derivative (JE22) with CD44 binding site. Cell viability, efficiency, and selectivity of drug release under acidic conditions together with CD44 binding capacity, effect on cell migration, and apoptotic activity were successfully evaluated. Remarkably, the conjugation of this CD44 inhibitor to the nanodevice generated a reduction of the dosis required to achieve a significant therapeutic effect.

A 5-FU Precursor Designed to Evade Anabolic and Catabolic Drug Pathways and Activated by Pd Chemistry In Vitro and In Vivo.

5-Fluorouracil (5-FU) is an antineoplastic antimetabolite that is widely administered to cancer patients by bolus injection, especially to those suffering from colorectal and pancreatic cancer. Because of its suboptimal route of administration and dose-limiting toxicities, diverse 5-FU prodrugs have been developed to confer oral bioavailability and increase the safety profile of 5-FU chemotherapy regimens. Our contribution to this goal is presented herein with the development of a novel palladium-activated prodrug designed to evade the metabolic machinery responsible for 5-FU anabolic activation and catabolic processing. The new prodrug is completely innocuous to cells and highly resistant to metabolization by primary hepatocytes and liver S9 fractions (the main metabolic route for 5-FU degradation), whereas it is rapidly converted into 5-FU in the presence of a palladium (Pd) source. In vivo pharmokinetic analysis shows the prodrug is rapidly and completely absorbed after oral administration and exhibits a longer half-life than 5-FU. In vivo efficacy studies in a xenograft colon cancer model served to prove, for the first time, that orally administered prodrugs can be locally converted to active drugs by intratumorally inserted Pd implants.

A minimally-masked inactive prodrug of panobinostat that is bioorthogonally activated by gold chemistry.

The recent incorporation of Au chemistry in the bioorthogonal toolbox has opened up new opportunities to deliver biologically independent reactions in living environments. Herein we report that the O-propargylation of the hydroxamate group of the potent HDAC inhibitor panobinostat leads to a vast reduction of its anticancer properties (>500-fold). We also show that this novel prodrug is converted back into panobinostat in the presence of Au catalysts in vitro and in cell culture.

Climacturia after robot-assisted laparoscopic radical prostatectomy / Climacturia tras prostatectomía radical laparoscópica asistida por robot

INTRODUCTION: Adverse effects in the sexual sphere are common in patients who have undergone radical prostatectomy (RP). Climacturia, involuntary loss of urine during orgasm, occurs in 20-40% of cases after PR. We analyse its prevalence and associated risk factors after Robotic-assisted laparoscopic radical prostatectomy (RALRP). OBJECTIVES: We analyse the climacturia prevalence after robotic-assisted laparoscopic radical prostatectomy (RALRP) and the association with other related factors. MATERIALS AND METHODS: Retrospective study of 100 patients underwent PRLAR from May 2011 to July 2014. After excluding patients who received radiotherapy after surgery (17), those who did not have sexual activity (7) and those with whom it could not be possible contacted (14), a structured telephone interview was conducted in 62 patients, investigating: presence and intensity of climacturia, orgasmic quality, incontinence and erectile dysfunction (ED). Other factors analysed included neurovascular preservation and rehabilitative treatment for ED. The statistical analysis consisted of Chi2test and logistic regression to evaluate associated factors. RESULTS: The mean age was 56 vs 59 years and the mean follow-up time was 26.6 vs 20.3 months, in the group with climacturia and without climacturia, respectively. The prevalence of climacturia was 17.9% (slight leaks-82% and severe leaks-18%). In 37% of these patients occurred in all orgasms. The quality of orgasm after surgery was worse in 47%, better in 13% and equal in 40%. The quality of the orgasm worsened more frequently in the climacturia group (63% vs 37%). The urinary incontinence rate was 41%, always effort incontinence. It was more frequent in patients with climacturia (62% vs 38%). In all patients with climacturia, bilateral neurovascular bundles preservation was performed. 32% of the patients had undergone post-surgical erectile rehabilitation with oral drugs. No statistically significant differences were found between patients with or without climacturia respect to the parameters analysed. CONCLUSIONS: Climacturia rate after PRLAR in our series was 17.9%. Patients with climacturia presented worse quality orgasms and a higher incontinence rate (p> 0.05). None of the analysed parameters could be defined as predictors of climacturia

INTRODUCCIÓN: Los efectos adversos en la esfera sexual son comunes en pacientes sometidos a prostatectomía radical (PR). La climaturia, pérdida involuntaria de orina durante el orgasmo, se presenta en un 20-40% de casos tras PR. Analizamos su prevalencia y asociación con otros factores relacionados tras prostatectomía radical laparoscópica asistida por robot (PRLAR). OBJETIVOS: Analizamos la prevalencia de climaturia tras PRLAR y su asociación con otros posibles factores riesgo relacionados. MATERIAL Y MÉTODOS: Estudio retrospectivo de 100 pacientes, sometidos a PRLAR desde mayo-2011 a julio-2014. Tras excluir a pacientes que recibieron radioterapia tras la cirugía (17), a los que no tenían actividad sexual (7) y aquellos con los que no se pudo contactar (14), se realizó entrevista telefónica estructurada a 62 pacientes, indagando sobre: presencia e intensidad de climaturia, calidad orgásmica, incontinencia y disfunción eréctil (DE). Otros factores analizados incluyeron la preservación neurovascular y el tratamiento rehabilitador para DE. El análisis estadístico consistió en prueba de Chi2 y regresión logística para evaluar factores asociados. RESULTADOS: La edad media fue 56 vs 59 años y el tiempo medio de seguimiento de 26,6 vs 20,3 meses, en el grupo con climaturia y sin climaturia respectivamente. La prevalencia de climaturia fue del 17.9% (pérdidas leves el 82% y severas el 18%). En el 37% de estos pacientes ocurrió en todos los orgasmos. La calidad del orgasmo tras cirugía fue peor en el 47%, mejor en el 13% e igual en el 40%. La calidad del orgasmo empeoró con más frecuencia en el grupo con climaturia (63% vs 37%). La tasa de incontinencia urinaria fue del 41%, siempre de esfuerzo. Fue más frecuente en pacientes con climaturia (62% vs 38%). El 68% de los pacientes usaba fármacos para DE. En todos los pacientes con climaturia se realizó preservación nerviosa bilateral. El 32% de los pacientes habían realizado rehabilitación eréctil postquirúrgica con fármacos orales. No se encontraron diferencias estadísticamente significativas entre pacientes con o sin climaturia respecto a los parámetros analizados. CONCLUSIONES: La tasa de climaturia tras PRLAR en nuestra serie fue del 17,9%. Los pacientes con climaturia presentaron orgasmos de peor calidad y una tasa de incontinencia superior (p > 0,05). Ninguno de los parámetros analizados pudieron definirse como factores predictivos de climaturia

Recent advances in the design of choline kinase α inhibitors and the molecular basis of their inhibition.

Upregulated choline metabolism, characterized by an increase in phosphocholine (PCho), is a hallmark of oncogenesis and tumor progression. Choline kinase (ChoK), the enzyme responsible for PCho synthesis, has consequently become a promising drug target for cancer therapy and as such a significant number of ChoK inhibitors have been developed over the last few decades. More recently, due to the role of this enzyme in other pathologies, ChoK inhibitors have also been used in new therapeutic approaches against malaria and rheumatoid arthritis. Here, we review research results in the field of ChoKα inhibitors from their synthesis to the molecular basis of their binding mode. Strategies for the development of inhibitors and their selectivity on ChoKα over ChoKß, the plasticity of the choline-binding site, the discovery of new exploitable binding sites, and the allosteric properties of this enzyme are highlighted. The outcomes summarized in this review will be a useful guide to develop new multifunctional potent drugs for the treatment of various human diseases.

Climacturia after robot-assisted laparoscopic radical prostatectomy.

INTRODUCTION: Adverse effects in the sexual sphere are common in patients who have undergone radical prostatectomy (RP). Climacturia, involuntary loss of urine during orgasm, occurs in 20-40% of cases after PR. We analyse its prevalence and associated risk factors after Robotic-assisted laparoscopic radical prostatectomy (RALRP). OBJECTIVES: We analyse the climacturia prevalence after robotic-assisted laparoscopic radical prostatectomy (RALRP) and the association with other related factors. MATERIALS AND METHODS: Retrospective study of 100 patients underwent PRLAR from May 2011 to July 2014. After excluding patients who received radiotherapy after surgery (17), those who did not have sexual activity (7) and those with whom it could not be possible contacted (14), a structured telephone interview was conducted in 62 patients, investigating: presence and intensity of climacturia, orgasmic quality, incontinence and erectile dysfunction (ED). Other factors analysed included neurovascular preservation and rehabilitative treatment for ED. The statistical analysis consisted of Chi2test and logistic regression to evaluate associated factors. RESULTS: The mean age was 56 vs 59 years and the mean follow-up time was 26.6 vs 20.3 months, in the group with climacturia and without climacturia, respectively. The prevalence of climacturia was 17.9% (slight leaks-82% and severe leaks-18%). In 37% of these patients occurred in all orgasms. The quality of orgasm after surgery was worse in 47%, better in 13% and equal in 40%. The quality of the orgasm worsened more frequently in the climacturia group (63% vs 37%). The urinary incontinence rate was 41%, always effort incontinence. It was more frequent in patients with climacturia (62% vs 38%). In all patients with climacturia, bilateral neurovascular bundles preservation was performed. 32% of the patients had undergone post-surgical erectile rehabilitation with oral drugs. No statistically significant differences were found between patients with or without climacturia respect to the parameters analysed. CONCLUSIONS: Climacturia rate after PRLAR in our series was 17.9%. Patients with climacturia presented worse quality orgasms and a higher incontinence rate (p> 0.05). None of the analysed parameters could be defined as predictors of climacturia.

Nondestructive production of exosomes loaded with ultrathin palladium nanosheets for targeted bio-orthogonal catalysis.

The use of exosomes as selective delivery vehicles of therapeutic agents, such as drugs or hyperthermia-capable nanoparticles, is being intensely investigated on account of their preferential tropism toward their parental cells. However, the methods used to introduce a therapeutic load inside exosomes often involve disruption of their membrane, which may jeopardize their targeting capabilities, attributed to their surface integrins. On the other hand, in recent years bio-orthogonal catalysis has emerged as a new tool with a myriad of potential applications in medicine. These bio-orthogonal processes, often based on Pd-catalyzed chemistry, would benefit from systems capable of delivering the catalyst to target cells. It is therefore highly attractive to combine the targeting capabilities of exosomes and the bio-orthogonal potential of Pd nanoparticles to create new therapeutic vectors. In this protocol, we provide detailed information on an efficient procedure to achieve a high load of catalytically active Pd nanosheets inside exosomes, without disrupting their membranes. The protocol involves a multistage process in which exosomes are first harvested, subjected to impregnation with a Pd salt precursor followed by a mild reduction process using gas-phase CO, which acts as both a reducing and growth-directing agent to produce the desired nanosheets. The technology is scalable, and the protocol can be conducted by any researcher having basic biology and chemistry skills in ~3 d.

Assessment of embryo implantation potential with a cloud-based automatic software.

RESEARCH QUESTION: Is embryo selection by Dana (automatic software for embryo evaluation) associated with a higher implantation rate in IVF treatments? DESIGN: A three-phase study for Dana system's validation: creation of a data-cloud of known implantation data (KID) embryos from 1676 transferred embryos; embryo evaluation by Dana considering manual annotations and embryo development videos (389 transferred embryos); and validation of Dana automatic selection, without embryologist's intervention (147 transferred embryos); RESULTS: The implantation rate of the 1021 KID embryos from phase 1 served to set four grades of embryos referring to implantation rate: A = 34%, B = 25%, C = 24%, and D = 19%. Phase 2: a classification ranking according to the unit average distance (UAD) and implantation potential was established: top (UAD ≤0.50), high (UAD = 0.51-0.66), medium (UAD = 0.67-1.03) and low (UAD >1.03). Pregnancy rates were 59%, 46%, 36% and 28%, respectively (P < 0.001). Phase 3: embryos were automatically categorized according to Dana's classification ranking. Most implanted embryos were found in groups top, high and medium (UAD ≤1.03), whereas the implantation rate in group low (UAD >1.03) was significantly lower: 46% versus 25%, respectively (P = 0.037). The twin gestation rate was higher when number of top embryos (UAD ≤0.5) transferred were two (52%) versus one (25%) (P < 0.001). CONCLUSIONS: Embryo selection based on Dana ranking increases the success of IVF treatments at least in oocyte donation programmes. The multicentre nature of the study supports its applicability at different clinics, standardizing the embryo development's interpretation. Dana's innovation is that the system increases its accuracy as the database grows.

Bioorthogonal Uncaging of Cytotoxic Paclitaxel through Pd Nanosheet-Hydrogel Frameworks.

The promising potential of bioorthogonal catalysis in biomedicine is inspiring incremental efforts to design strategies that regulate drug activity in living systems. To achieve this, it is not only essential to develop customized inactive prodrugs and biocompatible metal catalysts but also the right physical environment for them to interact and enable drug production under spatial and/or temporal control. Toward this goal, here, we report the first inactive precursor of the potent broad-spectrum anticancer drug paclitaxel (a.k.a. Taxol) that is stable in cell culture and labile to Pd catalysts. This new prodrug is effectively uncaged in cancer cell culture by Pd nanosheets captured within agarose and alginate hydrogels, providing a biodegradable catalytic framework to achieve controlled release of one of the most important chemotherapy drugs in medical practice. The compatibility of bioorthogonal catalysis and physical hydrogels opens up new opportunities to administer and modulate the mobility of transition metal catalysts in living environs.

Limitations of Standard Accessible Captioning of Sounds and Music for Deaf and Hard of Hearing People: An EEG Study.

Captioning is the process of transcribing speech and acoustical information into text to help deaf and hard of hearing people accessing to the auditory track of audiovisual media. In addition to the verbal transcription, it includes information such as sound effects, speaker identification, or music tagging. However, it just takes into account a limited spectrum of the whole acoustic information available in the soundtrack, and hence, an important amount of emotional information is lost when attending just to the normative compliant captions. In this article, it is shown, by means of behavioral and EEG measurements, how emotional information related to sounds and music used by the creator in the audiovisual work is perceived differently by normal hearing group and hearing disabled group when applying standard captioning. Audio and captions activate similar processing areas, respectively, in each group, although not with the same intensity. Moreover, captions require higher activation of voluntary attentional circuits, as well as language-related areas. Captions transcribing musical information increase attentional activity, instead of emotional processing.

Cancer-derived exosomes loaded with ultrathin palladium nanosheets for targeted bioorthogonal catalysis.

The transformational impact of bioorthogonal chemistries has inspired new strategies for the in vivo synthesis of bioactive agents through non-natural means. Among these, palladium (Pd) catalysts have played a prominent role in the growing subfield of bioorthogonal catalysis by producing xenobiotics and uncaging biomolecules in living systems. However, delivering catalysts selectively to specific cell types still lags behind catalyst development. Here we have developed a bio-artificial device consisting of cancer-derived exosomes loaded with Pd catalysts by a method that enables the controlled assembly of Pd nanosheets directly inside the vesicles. This hybrid system mediates Pd-triggered dealkylation reactions in vitro and inside cells and displays preferential tropism for their progenitor cells. The use of Trojan exosomes to deliver abiotic catalysts into designated cancer cells creates the opportunity for a new targeted therapy modality: exosome-directed catalyst prodrug therapy, whose first steps are presented herein with the cell-specific release of the anticancer drug panobinostat.

Demencia avanzada y decisiones difíciles: una oportunidad para la planificación de decisiones anticipadas / Advanced dementia and critical decisions: an opportunity for advanced care planning

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