Monastrol suppresses invasion and metastasis in human colorectal cancer cells by targeting fascin independent of kinesin-Eg5 pathway.

Rearrangement of the actin cytoskeleton is a prerequisite for carcinoma cells to develop cellular protrusions, which are required for migration, invasion, and metastasis. Fascin is a key protein involved in actin bundling and is expressed in aggressive and invasive carcinomas. Additionally, fascin appears to be involved in tubulin-binding and microtubule rearrangement. Pharmacophoric-based in silico screening was performed to identify compounds with better fascin inhibitory properties than migrastatin, a gold-standard fascin inhibitor. We hypothesized that monastrol displays anti-migratory and anti-invasive properties via fascin blocking in colorectal cancer cell lines. Biophysical (thermofluor and ligand titration followed by fluorescence spectroscopy), biochemical (NMR), and cellular assays (MTT, invasion of human tissue), as well as animal model studies (zebrafish invasion) were performed to characterize the inhibitory effect of monastrol on fascin activity. In silico analysis revealed that monastrol is a potential fascin-binding compound. Biophysical and biochemical assays demonstrated that monastrol binds to fascin and interferes with its actin-bundling activity. Cell culture studies, including a 3D human myoma disc model, showed that monastrol inhibited fascin-driven cytoplasmic protrusions as well as invasion. In silico, confocal microscopy, and immunoprecipitation assays demonstrated that monastrol disrupted fascin-tubulin interactions. These anti-invasive effects were confirmed in vivo. In silico confocal microscopy and immunoprecipitation assays were carried out to test whether monastrol disrupted the fascin-tubulin interaction. This study reports, for the first time, the in vitro and in vivo anti-invasive properties of monastrol in colorectal tumor cells. The number and types of interactions suggest potential binding of monastrol across actin and tubulin sites on fascin, which could be valuable for the development of antitumor therapies.

Accessible Eco-Friendly Method for Wastewater Removal of the Azo Dye Reactive Black 5 by Reusable Protonated Chitosan-Deep Eutectic Solvent Beads.

A novel approach to enhance the utilization of low-cost and sustainable chitosan for wastewater remediation is presented in this investigation. The study centers around the modification of chitosan beads using a deep eutectic solvent composed of choline chloride and urea at a molar ratio of 1:2, followed by treatment with sulfuric acid using an impregnation accessible methodology. The effectiveness of the modified chitosan beads as an adsorbent was evaluated by studying the removal of the azo dye Reactive Black 5 (RB5) from aqueous solutions. Remarkably, the modified chitosan beads demonstrated a substantial increase in adsorption efficiency, achieving excellent removal of RB5 within the concentration range of 25-250 mg/L, ultimately leading to complete elimination. Several key parameters influencing the adsorption process were investigated, including initial RB5 concentration, adsorbent dosage, contact time, temperature, and pH. Quantitative analysis revealed that the pseudo-second-order kinetic model provided the best fit for the experimental data at lower dye concentrations, while the intraparticle diffusion model showed superior performance at higher RB5 concentration ranges (150-250 mg/L). The experimental data were successfully explained by the Langmuir isotherm model, and the maximum adsorption capacities were found to be 116.78 mg/g at 298 K and 379.90 mg/g at 318 K. Desorption studies demonstrated that approximately 41.7% of the dye could be successfully desorbed in a single cycle. Moreover, the regenerated adsorbent exhibited highly efficient RB5 removal (80.0-87.6%) for at least five consecutive uses. The outstanding adsorption properties of the modified chitosan beads can be attributed to the increased porosity, surface area, and swelling behavior resulting from the acidic treatment in combination with the DES modification. These findings establish the modified chitosan beads as a stable, versatile, and reusable eco-friendly adsorbent with high potential for industrial implementation.

Venturi Injector Optimization for Precise Powder Transport for Directed Energy Deposition Manufacturing Using the Discrete Element Method and Genetic Algorithms.

Additive manufacturing technologies such as directed energy deposition use powder as their raw material, and it must be deposited in a precise and controlled manner. Venturi injectors could be a solution for the highly precise transport of particulate material. They have been studied from different perspectives, but they are always under high-pressure conditions and mostly fed by gravity. In the present study, an optimization of the different dimensional parameters needed for the manufacturing of a Venturi injector in relation to a particle has been carried out to maximize the amount of powder capable of being sucked and transported for a specific flow in a low-pressure system with high precision in transport. For this optimization, simulations of Venturi usage were performed using the discrete element method, generating different variations proposed by a genetic algorithm based on a preliminary design of experiments. Statistical analysis was also performed to determine the most influential design variables on the objective, with these being the suction diameter (D3), the throat diameter (d2), and the nozzle diameter (d1). The optimal dimensional relationships were as follows: a D3 34 times the particle diameter, a d2 26.5 times the particle diameter, a d1 40% the d2, a contraction angle alpha of 18.73°, and an expansion angle beta of 8.28°. With these proportions, an 85% improvement in powder suction compared to the initial attempts was achieved, with a maximum 2% loss of load.

[Cetoacidosis diabética al diagnóstico de diabetes mellitus tipo 1 en Asturias entre 2011 y 2020: influencia de la duración de los síntomas en la prevalencia de cetoacidosis y en la pérdida de peso.] / Diabetic ketoacidosis at diagnosis of type 1 diabetes in Asturias (Spain) between 2011 and 2020: influence of symptom duration on prevalence of ketoacidosis and weight loss.

OBJECTIVE: Diabetic ketoacidosis (DKA) is a serious complication that usually occurs at diagnosis of type 1 diabetes mellitus (T1D). However, the prevalence of DKA at diagnosis of T1D is heterogeneous in different regions of the world. The aim of this study was to determine the prevalence of DKA at diagnosis of T1D in Asturias. METHODS: This study included all patients under nineteen years of age diagnosed with T1D in Asturias between 2011 and 2020. Retrospective review of medical records was performed to analyse DKA and other characteristics at diagnosis. A log binary regression model was constructed to obtain an estimate of the prevalence ratio of DKA to diagnosis in the years studied. RESULTS: A total of 267 people were diagnosed with a mean age of 9.85±4.46 years. The prevalence of DKA at diagnosis during this period was 38.63%. There was an increasing trend, with a prevalence ratio over the years studied of 1.015 (95%CI: 0.96-1.07; p=0.61). Duration of symptoms before diagnosis was 4.57±7.64 weeks. Weight loss was 7.56±7.26%, being more than 10% of previous weight in almost half of the patients who loosed weight. There was a positive relationship between symptoms duration and prevalence of DKA and between time to diagnosis and weight loss. CONCLUSIONS: Asturias has a high prevalence of DKA at diagnosis of T1D, slightly higher than observed in other studies at national level and higher than in other similar countries, with a tendency to increase. Delayed diagnosis is a key factor in the prevalence of DKA and weight loss. Thus, health actions are needed for the early detection of T1D to avoid DKA at diagnosis.

OBJETIVO: La cetoacidosis diabética (CAD) es una complicación grave que puede producirse al diagnóstico de la diabetes mellitus tipo 1 (DM1). La prevalencia de CAD al diagnóstico de DM1 es desigual en las distintas regiones del mundo. El objetivo de este estudio fue conocer la prevalencia de CAD al diagnóstico de DM1 en Asturias. METODOS: Se incluyeron los pacientes menores de diecinueve años diagnosticados de DM1 en Asturias entre 2011 y 2020. Mediante revisión de historia clínica se analizó la prevalencia de CAD así como otras características al diagnóstico. Se construyó un modelo de regresión log binaria para obtener una estimación de la razón de prevalencia de CAD al diagnóstico en los años estudiados. RESULTADOS: Se diagnosticaron 267 personas con edad media de 9,85±4,46 años. La prevalencia de CAD al diagnóstico fue del 38,63%. Se apreció una tendencia al aumento, con una razón de prevalencia en los años estudiados de 1,015 (IC95%:0,96-1,07; p=0,61). La duración de los síntomas hasta el diagnóstico fue de 4,57±7,64 semanas. La pérdida de peso fue de 7,56±7,26%, siendo superior al 10% en casi la mitad de los pacientes que perdieron peso. Se apreció relación entre la duración de los síntomas y la prevalencia de CAD, y entre el tiempo de evolución y la pérdida de peso. CONCLUSIONES: Asturias presenta una alta prevalencia de CAD al diagnóstico de DM1, levemente superior a otros estudios a nivel nacional y superior a otros países de nuestro entorno, con tendencia al aumento. El retraso diagnóstico es clave en la prevalencia de CAD y en la pérdida de peso. Son necesarias actuaciones sanitarias para la detección precoz de la DM1.

Effect of the Combination of Hibiscus sabdariffa in Combination with Other Plant Extracts in the Prevention of Metabolic Syndrome: A Systematic Review and Meta-Analysis.

Metabolic syndrome is a complex and multifactorial disorder associated with increased risk of cardiovascular disease and type 2 diabetes, exacerbated by a sedentary lifestyle and situations such as the COVID-19 pandemic. Recent studies have shown that consumption of fruits and vegetables high in polyphenols has a protective effect, reducing cardiovascular risk. Hibiscus sabdariffa (HS) in combination with other plant extracts has recently attracted scientists' attention due to its potential use in the treatment of metabolic syndrome. This systematic review and meta-analysis examines the effects of HS in combination with other plant extracts on the prevention of metabolic syndrome, exploring their synergistic effects and potential as therapeutic agents. For this purpose, a systematic search of randomized clinical trials (RCTs) was conducted in four different databases and the data obtained were then used for a meta-analysis. Initially, the titles and abstracts of 1368 studies were read. From these, 16 studies were examined closely for their eligibility, and finally, seven RCTs with 332 participants were included in both the meta-analysis and the qualitative analysis. Our results show that HS in combination with other plant extracts improved anthropometric parameters, blood pressure, and lipid profile (low density lipoprotein cholesterol and total cholesterol) compared to a placebo control group. It is important to note that although this meta-analysis suggests that HS in combination with other plant extracts may have a beneficial effect on cardiovascular parameters, further research is needed to determine the optimal dose and intake duration.

A phase II randomised trial of abiraterone acetate plus prednisone in combination with docetaxel or docetaxel plus prednisone after disease progression to abiraterone acetate plus prednisone in patients with metastatic castration-resistant prostate cancer: The ABIDO-SOGUG trial.

BACKGROUND: We aimed to compare the efficacy and safety of maintaining or withdrawing abiraterone acetate plus prednisone (AAP) in patients with metastatic castration-resistant prostate cancer who had experienced cancer progression to this treatment and were beginning a docetaxel-based therapy. PATIENTS AND METHODS: Phase II, randomised, open-label study conducted in patients with metastatic castration-resistant prostate cancer who were asymptomatic or mildly symptomatic. After open-label treatment with AAP, patients who had experienced cancer progression to AAP were randomised to 75 mg/m2 of docetaxel plus AAP or to receive 75 mg/m2 of docetaxel plus 10 mg of prednisone orally daily. The primary outcome was the radiographic progression-free survival rate at 12 months as evaluated by the investigators in all randomised patients. RESULTS: A total of 148 patients were included in open-label treatment with AAP, and of them, 94 patients were randomised to receive either docetaxel plus AAP (intervention group; n = 47) or docetaxel plus prednisone (control group; n = 47). The 12-month radiographic progression-free survival rates did not differ between the intervention group (34.9%; 95% CI 20.7-49.2) and the control group (33.9%; 95% CI 19.5-48.3). There were no significant differences in the time to radiographic progression and the overall survival between the intervention and control groups. Grade 3-5 neutropenia with the combination of docetaxel plus prednisone and AA was more frequent than with docetaxel plus prednisone (59.6% versus 27.7%). CONCLUSION: Our results indicate that the therapeutic strategy of maintaining AAP added to docetaxel in chemotherapy-naïve patients who have experienced cancer progression to AAP treatment should not be further evaluated and should be avoided in clinical practice. CLINICAL TRIALS: NCT02036060 https://clinicaltrials.gov/ct2/show/NCT02036060.

Design of Personalized Neoantigen RNA Vaccines Against Cancer Based on Next-Generation Sequencing Data.

The good clinical results of immune checkpoint inhibitors (ICIs) in recent cancer therapy and the success of RNA vaccines against SARS-nCoV2 have provided important lessons to the scientific community. On the one hand, the efficacy of ICI depends on the number and immunogenicity of tumor neoantigens (TNAs) which unfortunately are not abundantly expressed in many cancer subtypes. On the other hand, novel RNA vaccines have significantly improved both the stability and immunogenicity of mRNA and its efficient delivery, this way overcoming past technique limitations and also allowing a quick vaccine development at the same time. These two facts together have triggered a resurgence of therapeutic cancer vaccines which can be designed to include individual TNAs and be synthesized in a timeframe short enough to be suitable for the tailored treatment of a given cancer patient.In this chapter, we explain the pipeline for the synthesis of TNA-carrying RNA vaccines which encompasses several steps such as individual tumor next-generation sequencing (NGS), selection of immunogenic TNAs, nucleic acid synthesis, drug delivery systems, and immunogenicity assessment, all of each step comprising different alternatives and variations which will be discussed.

Relevant SARS-CoV-2 viremia is associated with COVID-19 severity: Prospective cohort study and validation cohort.

Early kinetics of SARS-CoV-2 viral load (VL) in plasma determined by quantitative reverse-transcription polymerase chain reaction (RT-PCR) was evaluated as a predictor of poor clinical outcome in a prospective study and assessed in a retrospective validation cohort. Prospective observational single-center study including consecutive adult patients hospitalized with COVID-19 between November 2020 and January 2021. Serial plasma samples were obtained until discharge. Quantitative RT-PCR was performed to assess SARS-CoV-2 VL. The main outcomes were in-hospital mortality, admission to the Intensive Care Unit (ICU), and their combination (Poor Outcome). Relevant viremia (RV), established in the prospective study, was assessed in a retrospective cohort including hospitalized COVID-19 patients from April 2021 to May 2022, in which plasma samples were collected according to clinical criteria. Prospective cohort: 57 patients were included. RV was defined as at least a twofold increase in VL within ≤2 days or a VL > 300 copies/ml, in the first week. Patients with RV (N = 14; 24.6%) were more likely to die than those without RV (35.7% vs. 0%), needed ICU admission (57% vs. 0%) or had Poor Outcome (71.4% vs. 0%), (p < 0.001 for the three variables). Retrospective cohort: 326 patients were included, 18.7% presented RV. Patients with RV compared with patients without RV had higher rates of ICU-admission (odds ratio [OR]: 5.6 [95% confidence interval [CI]: 2.1-15.1); p = 0.001), mortality (OR: 13.5 [95% CI: 6.3-28.7]; p < 0.0001) and Poor Outcome (OR: 11.2 [95% CI: 5.8-22]; p < 0.0001). Relevant SARS-CoV-2 viremia in the first week of hospitalization was associated with higher in-hospital mortality, ICU admission, and Poor Outcome. Findings observed in the prospective cohort were confirmed in a larger validation cohort.

SARS-CoV-2 Viremia Precedes an IL6 Response in Severe COVID-19 Patients: Results of a Longitudinal Prospective Cohort.

Background: Interleukin 6 (IL6) levels and SARS-CoV-2 viremia have been correlated with COVID-19 severity. The association over time between them has not been assessed in a prospective cohort. Our aim was to evaluate the relationship between SARS-CoV-2 viremia and time evolution of IL6 levels in a COVID-19 prospective cohort. Methods: Secondary analysis from a prospective cohort including COVID-19 hospitalized patients from Hospital Universitario La Princesa between November 2020 and January 2021. Serial plasma samples were collected from admission until discharge. Viral load was quantified by Real-Time Polymerase Chain Reaction and IL6 levels with an enzyme immunoassay. To represent the evolution over time of both variables we used the graphic command twoway of Stata. Results: A total of 57 patients were recruited, with median age of 63 years (IQR [53-81]), 61.4% male and 68.4% Caucasian. The peak of viremia appeared shortly after symptom onset in patients with persistent viremia (more than 1 sample with > 1.3 log10 copies/ml) and also in those with at least one IL6 > 30 pg/ml, followed by a progressive increase in IL6 around 10 days later. Persistent viremia in the first week of hospitalization was associated with higher levels of IL6. Both IL6 and SARS-CoV-2 viral load were higher in males, with a quicker increase with age. Conclusion: In those patients with worse outcomes, an early peak of SARS-CoV-2 viral load precedes an increase in IL6 levels. Monitoring SARS-CoV-2 viral load during the first week after symptom onset may be helpful to predict disease severity in COVID-19 patients.

Single-nucleotide polymorphism associations with efficacy and toxicity in metastatic castration-resistant prostate cancer treated with cabazitaxel.

Background: The aim of this study was to evaluate the impact of certain single-nucleotide polymorphisms (SNPs) in cabazitaxel activity and toxicity in patients with metastatic castration-resistant prostate cancer (mCRPC). Patients & methods: 56 SNPs in five genes (CYP3A4, CYP3A5, ABCB1, TUBB1 and CYP2C8) were genotyped in 67 mCRPC patients and their correlation with outcomes analyzed. Results:TUBB1-rs151352 (hazard ratio: 0.52) and CYP2C8-rs1341164 (hazard ratio: 0.53) were associated with better overall survival, and CYP2C8-rs1058932 with biochemical progression (odds ratio: 6.60) in multivariate analysis. ABCB1-rs17327624 correlated with severe toxicity ≥grade 3 (odds ratio: 8.56) and CYP2C8-rs11572093 with asthenia (odds ratio: 8.12). Conclusion: Genetic variants in mCRPC patients could explain different outcomes with cabazitaxel. Nonetheless, the small sample size and the high number of SNPs analyzed mean that the results are only hypothesis-generating and require further validation.

Objective space division-based hybrid evolutionary algorithm for handing overlapping solutions in combinatorial problems.

Overlapping solutions occur when more than one solution in the space of decisions maps to the same solution in the space of objectives. This situation threatens the exploration capacity of Multi-Objective Evolutionary Algorithms (MOEAs), preventing them from having a good diversity in their population. The influence of overlapping solutions is intensified on multi-objective combinatorial problems with a low number of objectives. This paper presents a hybrid MOEA for handling overlapping solutions that combines the classic NSGA-II with a strategy based on Objective Space Division (OSD). Basically, in each generation of the algorithm, the objective space is divided into several regions using the nadir solution calculated from the current generation solutions. Furthermore, the solutions in each region are classified into non-dominated fronts using different optimization strategies in each of them. This significantly enhances the achieved diversity of the approximate front of non-dominated solutions. The proposed algorithm (called NSGA-II/OSD) is tested on a classic Operations Research problem: the Multi-Objective Knapsack Problem (0-1 MOKP) with two objectives. Classic NSGA-II, MOEA/D and Global WASF-GA are used to compare the performance of NSGA-II/OSD. In the case of MOEA/D two different versions are implemented, each of them with a different strategy for specifying the reference point. These MOEA/D reference point strategies are thoroughly studied and new insights are provided. This paper analyses in depth the impact of overlapping solutions on MOEAs, studying the number of overlapping solutions, the number of solution repairs, the hypervolume metric, the attainment surfaces and the approximation to the real Pareto front, for different sizes of 0-1 MOKPs with two objectives. The proposed method offers very good performance when compared to the classic NSGA-II, MOEA/D and Global WASF-GA algorithms, all of them well-known in the literature.

Self-expandable metal stents versus endoscopic balloon dilation for the treatment of strictures in Crohn's disease (ProtDilat study): an open-label, multicentre, randomised trial.

BACKGROUND: Endoscopic balloon dilation (EBD) is the established endoscopic treatment for short strictures in Crohn's disease. Fully covered self-expandable metal stents (FCSEMS) have been used for endoscopic treatment of patients for whom EBD was unsuccessful. We aimed to determine the efficacy and safety of the two endoscopic treatments in patients with Crohn's disease with stenosis and compare the mean cost of both treatments. METHODS: This multicentre, open-label, randomised trial was done in 19 tertiary and secondary hospitals in Spain. Patients with Crohn's disease with obstructive symptoms and predominantly fibrotic strictures of less than 10 cm in length were eligible for inclusion. We excluded patients with stenosis treated with SEMS or EBD in the previous year and stenosis not accessible to a colonoscope. Patients were randomly assigned (1:1) to receive either EBD (EBD group) or FCSEMS (FCSEMS group) using a digital en-block randomisation system (block size of four). In the EBD group, dilation was done with a CRE Boston Scientific (Marlborough, MA, USA) pneumatic balloon with the diameter set at the discretion of the endoscopist; a maximum of two sessions of dilation were allowed with a minimum interval of 15-30 days between them. In the FCSEMS group, a 20 mm diameter Taewoong (Gimpo-si, South Korea) fully covered metal stent was placed; stent length was set at the discretion of the endoscopist. The primary outcome was to assess the efficacy of the endoscopic treatment, defined by the proportion of patients free of a new therapeutic intervention (EBD, FCSEMS, or surgery) due to symptomatic recurrence at 1 year of follow-up. Patients were analysed according to the intention-to-treat principle. Adverse events were recorded for all the patients; events were considered associated to be with the procedure when a causal association was possible, probable, or definite. This trial is registered with ClinicalTrials.gov, NCT02395354. FINDINGS: From Aug 28, 2013, to Oct 9, 2017, we assessed the eligibility of 99 patients, of whom 19 (19%) patients were excluded. Thus, 80 (81%) patients were randomly assigned to treatment: 39 (49%) patients to the FCSEMS group and 41 (51%) patients to the EBD group. 33 (80%) of 41 patients in the EBD group and 20 (51%) of 39 patients in the FCSEMS group were free of a new therapeutic intervention at 1 year (odds ratio [OR] 3·9 [95% CI 1·4-10·6]; p=0·0061). Two (3%) of 80 patients had severe adverse events (one [2%] patient in the EBD group and one [3%] patient in the FCSEMS group); both patients had perforations. INTERPRETATION: EBD is more effective than FCSEMS for Crohn's disease strictures, with a good safety profile for both treatments. FUNDING: Spanish National Institute of Health, Foundation of Spanish Society of Digestive Endoscopy, Catalan Society of Gastroenterology, and Taweoong.

Comparison of Patients With Total and Salvage Laryngectomy.

INTRODUCTION AND OBJECTIVES: Total laryngectomy (TL) is one of the treatments available in locally advanced laryngeal carcinomas or as a salvage therapy when organ preservation fails, achieving high survival rates and few complications. The aim of this study was to analyse the oncological outcomes, comparing the data obtained with the current literature and analysing complications and survival. METHODS: The study included 62 patients with primary carcinoma of the larynx treated by primary or salvage TL between 2003 and 2019. We analysed the demographic, clinical and pathological characteristics, tumour stage, complementary treatments, postoperative complications, locoregional recurrences, metastases, and causes of death. RESULTS: The mean age was 64 years, 90.3% were men, 96.8% were smokers, 43.5% had multiple pathologies and 82.3% had a locally advanced stage. Of all TL 71% were primary and 29% salvage. Neck dissection was performed in 59.6%. Lymphovascular invasion was present in 30.6%, perineural invasion in 30.6% and margin involvement in 14.5%. During the follow-up, 17.7% presented locoregional recurrence and 11.3% distant metastases. Regarding complementary treatments, 56.4% of the patients received adjuvant therapy. The incidence of haemorrhage was 11.3%, infection 14.5%, and pharyngocutaneous fistula 21%. There was a statistically significant correlation between fistula and haemorrhage (P = .000) and between fistula and infection (P = .000). No statistically significant differences were found between the studied factors of primary and salvage TL. The 3-year overall survival was 92% and 5-year overall survival was 88%, finding statistical significance with the locally advanced stage (P = .038), T4 (P = .026), lymphovascular invasion (P = .019) and the involvement of more than 3 lymph nodes in the pathological anatomy (P = .005). On the multivariate analysis, the only variable that showed a significant relationship with survival was lymphovascular invasion (P = .026). CONCLUSIONS: Although organ preservation is a primary objective, TL remains a leading treatment in locally advanced carcinomas and as salvage in case of failure of medical therapy or partial surgery.

Combining microfluidics with machine learning algorithms for RBC classification in rare hereditary hemolytic anemia.

Combining microfluidics technology with machine learning represents an innovative approach to conduct massive quantitative cell behavior study and implement smart decision-making systems in support of clinical diagnostics. The spleen plays a key-role in rare hereditary hemolytic anemia (RHHA), being the organ responsible for the premature removal of defective red blood cells (RBCs). The goal is to adapt the physiological spleen filtering strategy for in vitro study and monitoring of blood diseases through RBCs shape analysis. Then, a microfluidic device mimicking the slits of the spleen red pulp area and video data analysis are combined for the characterization of RBCs in RHHA. This microfluidic unit is designed to evaluate RBC deformability by maintaining them fixed in planar orientation, allowing the visual inspection of RBC's capacity to restore their original shape after crossing microconstrictions. Then, two cooperative learning approaches are used for the analysis: the majority voting scheme, in which the most voted label for all the cell images is the class assigned to the entire video; and the maximum sum of scores to decide the maximally scored class to assign. The proposed platform shows the capability to discriminate healthy controls and patients with an average efficiency of 91%, but also to distinguish between RHHA subtypes, with an efficiency of 82%.

The FDA-Approved Antiviral Raltegravir Inhibits Fascin1-Dependent Invasion of Colorectal Tumor Cells In Vitro and In Vivo.

BACKGROUND: Fascin1 is the key actin-bundling protein involved in cancer invasion and metastasis whose expression is associated with bad prognosis in tumor from different origins. METHODS: In the present study, virtual screening (VS) was performed for the search of Fascin1 inhibitors and RAL, an FDA-approved inhibitor of human immunodeficiency virus-1 (HIV-1) integrase, was identified as a potential Fascin1 inhibitor. Biophysical techniques including nuclear magnetic resonance (NMR) and differential scanning fluorimetry (DSF) were carried out in order to confirm RAL as a Fascin1 blocker. The effect of RAL on actin-bundling activity Fascin1 was assessed by transmission electron microscopy (TEM), immunofluorescence, migration, and invasion assays on two human colorectal adenocarcinoma cell lines: HCT-116 and DLD-1. In addition, the anti-metastatic potential of RAL was in vivo evaluated by using the zebrafish animal model. RESULTS: NMR and DSF confirmed in silico predictions and TEM demonstrated the RAL-induced disorganization of the actin structure compared to control conditions. The protrusion of lamellipodia in cancer cell line overexpressing Fascin1 (HCT-116) was abolished in the presence of this drug. By following the addition of RAL, migration of HCT-116 and DLD-1 cell lines was significantly inhibited. Finally, using endogenous and exogenous models of Fascin1 expression, the invasive capacity of colorectal tumor cells was notably impaired in the presence of RAL in vivo assays; without undesirable cytotoxic effects. CONCLUSION: The current data show the in vitro and in vivo efficacy of the antiretroviral drug RAL in inhibiting human colorectal cancer cells invasion and metastasis in a Fascin1-dependent manner.

Comparison of patients with total and salvage laryngectomy. / Comparación de pacientes con laringectomía total primaria y de rescate.

INTRODUCTION AND OBJECTIVES: Total laryngectomy (TL) is one of the treatments available in locally advanced laryngeal carcinomas or as a salvage therapy when organ preservation fails, achieving high survival rates and few complications. The aim of this study was to analyse the oncological outcomes, comparing the data obtained with the current literature and analysing complications and survival. METHODS: The study included 62 patients with primary carcinoma of the larynx treated by primary or salvage TL between 2003 and 2019. We analysed the demographic, clinical and pathological characteristics, tumour stage, complementary treatments, postoperative complications, locoregional recurrences, metastases, and causes of death. RESULTS: The mean age was 64 years, 90.3% were men, 96.8% were smokers, 43.5% had multiple pathologies and 82.3% had a locally advanced stage. Of all TL 71% were primary and 29% salvage. Neck dissection was performed in 59.6%. Lymphovascular invasion was present in 30.6%, perineural invasion in 30.6% and margin involvement in 14.5%. During the follow-up, 17.7% presented locoregional recurrence and 11.3% distant metastases. Regarding complementary treatments, 56.4% of the patients received adjuvant therapy. The incidence of haemorrhage was 11.3%, infection 14.5%, and pharyngocutaneous fistula 21%. There was a statistically significant correlation between fistula and haemorrhage (P=.000) and between fistula and infection (P=.000). No statistically significant differences were found between the studied factors of primary and salvage TL. The 3-year overall survival was 92% and 5-year overall survival was 88%, finding statistical significance with the locally advanced stage (P=.038), T4 (P=.026), lymphovascular invasion (P=.019) and the involvement of more than 3 lymph nodes in the pathological anatomy (P=.005). On the multivariate analysis, the only variable that showed a significant relationship with survival was lymphovascular invasion (P=.026). CONCLUSIONS: Although organ preservation is a primary objective, TL remains a leading treatment in locally advanced carcinomas and as salvage in case of failure of medical therapy or partial surgery.

rUTI Resolution After FMT for Clostridioides difficile Infection: A Case Report.

Clostridioides difficile infection (CDI) is the leading cause of nosocomial infectious diarrhea. Fecal microbiota transplantation (FMT) is a successful treatment for recurrent CDI (rCDI), and in some patients FMT has been associated with the resolution of recurrent urinary tract infections (rUTI). Recent evidence suggests that the origin of most bacterial infections in the urinary tract is the gut. Thus, the possibility of using FMT to displace pathogens commonly involved in rUTIs has major therapeutic implications. We report the case of a 93-year-old female patient with a rCDI and rUTI that underwent FMT and reported a complete clinical resolution of CDI; unexpectedly, no new symptomatic UTI episodes were diagnosed post-FMT. We characterized the gut microbiota of the stool donor and of the patient before and after the procedure. Our patient presented a dysbiosis with clear predominance of Enterobacteriaceae (74%) before FMT, which was significantly reduced to 0.07% after FMT. These findings were maintained for almost a year. We also observed an increase in microbial diversity indices compared with the pre-FMT sample reaching diversity values comparable to the donor stool samples. We reasoned that the disappearance of UTIs in our patient resulted from the reduction of Enterobacteriaceae in the gut microbiota. Our findings support previous evidence suggesting the potential of FMT for rUTI, particularly in cases due to multi-drug resistant pathogens where conventional antibiotic treatment is not an option.

Small Bowel Enteroscopy - A Joint Clinical Guideline from the Spanish and Portuguese Small Bowel Study Groups.

The present evidence-based guidelines are focused on the use of device-assisted enteroscopy in the management of small-bowel diseases. A panel of experts selected by the Spanish and Portuguese small bowel study groups reviewed the available evidence focusing on the main indications of this technique, its role in the management algorithm of each indication and on its diagnostic and therapeutic yields. A set of recommendations were issued accordingly.

Estas recomendações baseadas na evidência detalham o uso da enteroscopia assistida por dispositivo no manejo clínico das doenças do intestino delgado. Um conjunto de Gastrenterologistas diferenciados em patologia do intestino delgado foi selecionado pelos grupos de estudos Espanhol e Portugués de intestino delgado para rever a evidência disponível sobre as principais indicações desta técnica, o seu papel nos algoritmos de manejo de cada indicação e sobre o seu rendimento diagnóstico e terapêutico. Foi gerado um conjunto de recomendações pelos autores.

Final Overall Survival Analysis of the SOGUG Phase 2 MAJA Study: Maintenance Vinflunine Versus Best Supportive Care After First-Line Chemotherapy in Advanced Urothelial Carcinoma.

INTRODUCTION: The MAJA study compared vinflunine (VFL) plus best supportive care (BSC) maintenance therapy versus BSC alone in advanced urothelial carcinoma responsive to first-line chemotherapy. The primary end point of progression-free survival was achieved. We present the final overall survival (OS) and long-term follow-up safety analyses. PATIENTS AND METHODS: Patients were enrolled, and a subsequent post hoc analysis was performed on the basis of radiologic response or stabilization to first-line cisplatin/gemcitabine (CG) chemotherapy (4-6 cycles), according to Response Evaluation Criteria in Solid Tumors (RECIST). VFL + BSC versus BSC alone were randomly assigned until disease progression. RESULTS: At final analysis, 58 patients (66.7%) had died while 29 (33.3%) had survived; the BSC arm had higher mortality (VFL + BSC, n = 26, 59.1% vs. BSC, n = 32, 74.4%). Median follow-up of surviving patients was 38.8 months (interquartile range, 23.8-61.6). Median OS was 16.7 months (95% confidence interval, 0-34.5) in VFL and 13.2 months (95% confidence interval, 6-20.4) in the BSC groups (hazard ratio, 0.736; 95% confidence interval, 0.44-1.24, P = .182). Post hoc group division did not affect median OS in either study arm. CONCLUSION: Final analysis supported a benefit of VFL in maintenance therapy in patients with disease control after first-line treatment with CG, with no unexpected long-term adverse effects. The study was insufficiently powered to show a significant OS advantage.