Polyvalent Bacterial Lysate with Potential Use to Treatment and Control of Recurrent Urinary Tract Infections.

Overuse of antimicrobials has greatly contributed to the increase in the emergence of multidrug-resistant bacteria, a situation that hinders the control and treatment of infectious diseases. This is the case with urinary tract infections (UTIs), which represent a substantial percentage of worldwide public health problems, thus the need to look for alternatives for their control and treatment. Previous studies have shown the usefulness of autologous bacterial lysates as an alternative for the treatment and control of UTIs. However, a limitation is the high cost of producing individual immunogens. At the same time, an important aspect of vaccines is their immunogenic amplitude, which is the reason why they must be constituted of diverse antigenic components. In the case of UTIs, the etiology of the disease is associated with different bacteria, and even Escherichia coli, the main causal agent of the disease, is made up of several antigenic variants. In this work, we present results on the study of a bacterial lysate composed of 10 serotypes of Escherichia coli and by Klebsiella pneumoniae, Klebsiella aerogenes, Enterococcus faecalis, Proteus mirabilis, Citrobacter freundii, and Staphylococcus haemolyticus. The safety of the compound was tested on cells in culture and in an animal model, and its immunogenic capacity by analysing in vitro human and murine macrophages (cell line J774 A1). The results show that the polyvalent lysate did not cause damage to the cells in culture or alterations in the animal model used. The immunostimulatory activity assay showed that it activates the secretion of TNF-α and IL-6 in human macrophages and TNF-α in murine cells. The obtained results suggest that the polyvalent lysate evaluated can be an alternative for the treatment and control of chronic urinary tract infections, which will reduce the use of antimicrobials.

Statistical image reconstruction with beam-hardening compensation for X-ray CT by a calibration step (2DIterBH).

BACKGROUND: The beam-hardening effect due to the polychromatic nature of the X-ray spectra results in two main artifacts in CT images: cupping in homogeneous areas and dark bands between dense parts in heterogeneous samples. Post-processing methods have been proposed in the literature to compensate for these artifacts, but these methods may introduce additional noise in low-dose acquisitions. Iterative methods are an alternative to compensate noise and beam-hardening artifacts simultaneously. However, they usually rely on the knowledge of the spectrum or the selection of empirical parameters. PURPOSE: We propose an iterative reconstruction method with beam hardening compensation for small animal scanners that is robust against low-dose acquisitions and that does not require knowledge of the spectrum, overcoming the limitations of current beam-hardening correction algorithms. METHODS: The proposed method includes an empirical characterization of the beam-hardening function based on a simple phantom in a polychromatic statistical reconstruction method. Evaluation was carried out on simulated data with different noise levels and step angles and on limited-view rodent data acquired with the ARGUS/CT system. RESULTS: Results in small animal studies showed a proper correction of the beam-hardening artifacts in the whole sample, independently of the quantity of bone present on each slice. The proposed approach also reduced noise in the low-dose acquisitions and reduced streaks in the limited-view acquisitions. CONCLUSIONS: Using an empirical model for the beam-hardening effect, obtained through calibration, in an iterative reconstruction method enables a robust correction of beam-hardening artifacts in low-dose small animal studies independently of the bone distribution.

Control de diabetes y consultas al médico de familia durante la pandemia de COVID-19: estudio multicéntrico en atención primaria / Diabetes control and visits to the family doctor during the COVID-19 pandemic: a multicenter study in primary care

Objetivos: Determinar los cambios de frecuentación de consultas presenciales (CP) y telemáticas (CT) a su médico de familia en pacientes con diabetes tipo 2 (DM2) durante la pandemia de COVID-19 y su relación con el control de su enfermedad. Diseño: Estudio multicéntrico de seguimiento retrospectivo. Emplazamiento: Siete centros de salud en Tenerife, España. Participantes: Un total de 3.543 pacientes con DM2. Mediciones: Sexo, edad, CP, CT y control de DM2 mediante hemoglobina glicosilada (A1c) durante el periodo 2019-2021. Se ajustaron modelos de regresión logística con el control de DM2 como efecto, y con las demás mediciones como variables independientes. Resultados: El 50% eran mujeres. El 38% tenía 65 años o menos. Se midió la A1c al 84% de los pacientes en 2019, 68% en 2020, y 77% en 2021. Presentaron buen control el 58,4% en 2019, 46,1% en 2020 y 50,3% en 2021. Las CP fueron 7 en 2019, 4 en 2020 y 5 en 2021 (p<0,001). Las razones de ventaja (IC95%) de buen control en 2019 fueron 1,04 (1,04-1,05) por cada año más de edad y 1,03 (1,01-1,04) por cada CP más; en 2020 fueron 1,04 (1,03-1,05) por cada año más de edad, 1,05 (1,04-1,07) por cada CP más y 1,04 (1,02-1,07) por cada CT más; en 2021 fueron 1,04 (1,04-1,05) por cada año más de edad, 1,05 (1,03-1,06) por cada CP más y 1,02 (1,00-1,04) por cada CT más. Conclusiones: El control de pacientes con DM2 durante 2019-2021 tuvo una relación directa con el cambio de frecuentación al centro de salud, con diferencias según el tipo de consulta y la edad.(AU)

Objectives: To determine whether in patients with type 2 diabetes (DM2) the changes in their relationship with family doctors during the COVID-19 pandemic, in-person (iPC) and telematic (TC) consultations, were associated with control of their disease. Design: Multicentric study of retrospective follow-up. Setting: Seven health centers in Tenerife, Spain. Participants: 3543 patients with DM2. Main measurements: Sex, age, iPC, TC and DM2 control using glycosylated hemoglobin (A1c) during the period 2019-2021. Logistic regression models were fitted with DM2 control as an effect, and with the other measurements as independent variables. Results: 50% were women. 38% were less than 65 years old. A1c was measured in 84% of patients in 2019, 68% in 2020, and 77% in 2021. 58.4% had good control in 2019, 46.1% in 2020, and 50.3% in 2021. Median iPC were 7 in 2019, 4 in 2020 and 5 in 2021 (p<0.001). The OR(95%CI) of good control in 2019 were 1.04(1.04-1.05) per year of age and 1.03(1.01-1.04) for each iPC; In 2020 they were 1.04 (1.03-1.05) per year of age, 1.05 (1.04-1.07) for each iPC and 1.04 (1.02-1.07) for each TC; in 2021 they were 1.04 (1.04-1.05) per year of age, 1.05 (1.03-1.06) for each iPC and 1.02 (1.00-1.04) for each TC. Conclusions: The control of patients with DM2 during the period 2019-2021 had a direct relationship with the change in the frequency of consultations at the health center, with differences depending on the type of consultation and the age of the patient.(AU)

[Diabetes control and visits to the family doctor during the COVID-19 pandemic: a multicenter study in primary care]. / Control de diabetes y consultas al médico de familia durante la pandemia de COVID-19: estudio multicéntrico en atención primaria.

OBJECTIVES: To determine whether in patients with type 2 diabetes (DM2) the changes in their relationship with family doctors during the COVID-19 pandemic, in-person (iPC) and telematic (TC) consultations, were associated with control of their disease. DESIGN: Multicentric study of retrospective follow-up. SETTING: Seven health centers in Tenerife, Spain. PARTICIPANTS: 3543 patients with DM2. MAIN MEASUREMENTS: Sex, age, iPC, TC and DM2 control using glycosylated hemoglobin (A1c) during the period 2019-2021. Logistic regression models were fitted with DM2 control as an effect, and with the other measurements as independent variables. RESULTS: 50% were women. 38% were less than 65 years old. A1c was measured in 84% of patients in 2019, 68% in 2020, and 77% in 2021. 58.4% had good control in 2019, 46.1% in 2020, and 50.3% in 2021. Median iPC were 7 in 2019, 4 in 2020 and 5 in 2021 (p<0.001). The OR(95%CI) of good control in 2019 were 1.04(1.04-1.05) per year of age and 1.03(1.01-1.04) for each iPC; In 2020 they were 1.04 (1.03-1.05) per year of age, 1.05 (1.04-1.07) for each iPC and 1.04 (1.02-1.07) for each TC; in 2021 they were 1.04 (1.04-1.05) per year of age, 1.05 (1.03-1.06) for each iPC and 1.02 (1.00-1.04) for each TC. CONCLUSIONS: The control of patients with DM2 during the period 2019-2021 had a direct relationship with the change in the frequency of consultations at the health center, with differences depending on the type of consultation and the age of the patient.

Rational optimization of a transcription factor activation domain inhibitor.

Transcription factors are among the most attractive therapeutic targets but are considered largely 'undruggable' in part due to the intrinsically disordered nature of their activation domains. Here we show that the aromatic character of the activation domain of the androgen receptor, a therapeutic target for castration-resistant prostate cancer, is key for its activity as transcription factor, allowing it to translocate to the nucleus and partition into transcriptional condensates upon activation by androgens. On the basis of our understanding of the interactions stabilizing such condensates and of the structure that the domain adopts upon condensation, we optimized the structure of a small-molecule inhibitor previously identified by phenotypic screening. The optimized compounds had more affinity for their target, inhibited androgen-receptor-dependent transcriptional programs, and had an antitumorigenic effect in models of castration-resistant prostate cancer in cells and in vivo. These results suggest that it is possible to rationally optimize, and potentially even to design, small molecules that target the activation domains of oncogenic transcription factors.

Real-world effectiveness and persistence of secukinumab in the treatment of patients with psoriatic arthritis.

Introduction: Psoriatic arthritis (PsA) is a complex and heterogeneous inflammatory disease. Secukinumab, a biologic disease-modifying antirheumatic drug (bDMARD), has extensive clinical evidence of efficacy and safety in the treatment of PsA but data in clinical practice are still limited. This study aims to provide real-world evidence on secukinumab use, effectiveness, and persistence in PsA. Methods: A retrospective, multicenter study was conducted on patients diagnosed with PsA and treated with secukinumab up to June 2021 at 12 centers in the Valencian Community (Spain). Data on DAS28-CRP, DAPSA, Tender and Swollen Joint Counts (TJC, SJC), enthesitis, dactylitis, skin and nail involvement, pain, patient and physician global assessment (ptGA, phGA) using 100-mm visual analog scale (VAS), and persistence for up to 24 months were collected. Results: A total of 178 patients were included (49% men; mean [standard deviation, SD] age: 51.4 [10.5] years; 39% obese). Secukinumab was used as a first-, second-, or ≥ third-line bDMARD in 37, 21, and 42% of patients, respectively. The percentage of patients achieving at least low disease activity (DAS28-CRP ≤ 3.2) increased from 25% at baseline to 66% at month 6 (M6) and was maintained (75%) up to M24. Mean (SD) DAS28-CRP baseline values (3.9 [1.2]) decreased to 2.9 (1.1) (p < 0.001) at M6 and remained low through M24 (2.6 [1.1]) (p < 0.001). Secukinumab also improved peripheral arthritis increasing the percentage of patients with TJC = 0 (20% baseline; 57% M24) and SJC = 0 (37% baseline; 80% M24). Treatment reduced the percentage of patients with enthesitis (25% baseline; 6% M24), dactylitis (20% baseline; 4% M24), and skin (70% baseline; 17% M24), and nail (32% baseline; 2% M24) involvement. Additionally, we observed improvements in the mean pain VAS (-26.4 mm M24), ptGA (-26.2 mm M24), and phGA (-24.8 mm M24). Secukinumab showed an overall 24-month persistence rate of 67% (95% confidence interval [CI]: 60-74%). Patients receiving first-line secukinumab showed the highest 24-month persistence rate (83, 95% CI: 73-92; p = 0.024). Conclusion: Secukinumab showed long-term effectiveness across the six key PsA domains thus reducing disease activity and pain, which are major treatment goals. This was accompanied by high persistence rates, especially in bDMARD naive patients.

Real-world experience with secukinumab in the entire axial spondyloarthritis spectrum.

Background: Secukinumab is a biologic disease-modifying antirheumatic drug (bDMARD) that has demonstrated efficacy in the treatment of axial spondyloarthritis (axSpA, i.e., ankylosing spondylitis and non-radiographic axSpA) across various clinical trials. However, data of secukinumab in clinical practice is still limited. Here, we aimed to provide real-world data on secukinumab use, effectiveness, and persistence in axSpA. Patients and methods: Retrospective, multicenter study of patients with a diagnosis of axSpA treated with secukinumab at 12 centers up to June 2021 in the Valencian Community (Spain). Information was gathered on BASDAI measurement, pain, patient and physician global assessment (ptGA, phGA) using a 100-mm visual analog scale (VAS), persistence and other secondary variables by treatment line (first, second, and ≥ third) for up to 24 months. Results: 221 patients were included (69% men; mean age [standard deviation, SD]: 46.7 [12.1] years old). Secukinumab was used as a first-line bDMARD in 38% of patients, as a second-line in 34% and as a ≥ hird-line in 28%. The percentage of patients achieving low disease activity (BASDAI<4) increased from 9% at baseline to 48% at month 6 and was maintained (49%) up to month 24. The greatest improvement in BASDAI was observed in naïve patients (month 6: -2.6; month 24: -3.7), followed by second-line (month 6: -1.9; month 24: -3.1) and ≥ third-line (month 6: -1.3; month 24: -2.3) patients. Reductions in mean pain VAS (-23.3; -31.9), ptGA (-25.1; -31.9) and phGA (-25.1; -31) were also observed at 6 and 24 months. Secukinumab showed an overall 12-months persistence rate of 70% (95% confidence interval [CI]: 63-77%) and a 24-months persistence rate of 58% (95% CI, 51-66%). Patients receiving first-line secukinumab had the highest 24-months persistence rate (p = 0.05). Conclusion: Secukinumab improved disease activity in axSpA patients, especially in naive, and second-line patients, which was accompanied by high persistence rates up to 24 months.

All-Arthroscopic Triangular Fibrocartilage Complex Ligamentoplasty: Technique and Results.

Objective The aim of the study is to describe the modified all-arthroscopic technique for triangular fibrocartilage complex (TFCC) ligamentoplasty in chronic injuries of the TFCC with distal radioulnar joint (DRUJ) instability, and to present the results obtained. Methods A prospective study was conducted including 11 consecutive patients with chronic TFCC injury with DRUJ instability who underwent an all-arthroscopic TFCC ligamentoplasty. During follow-up, the range of joint motion, grip strength, pain according to the visual analog scale (VAS), functional outcomes according to the Mayo Wrist Score (MWS), and the QuickDASH Score were measured, and any complications and necessary reinterventions were recorded Results We analyzed 11 patients with distal radioulnar ligament injury treated using the all-arthroscopic ligamentoplasty technique. Mean follow-up was 31.5 ± 4.4 (range 12-58) months. The technique presented achieved DRUJ stability in 100% of cases at 12 months. Grip strength and pain, showed a statistically significant improvement between the preoperative score and the two postoperative assessments. Functional assessment using the QuickDASH score and the MWS also improved significantly. Conclusion The all-arthroscopic technique for the reconstruction of irreparable peripheral TFCC tears is a reliable technique, intended not only to minimize the surgical trauma to reduce postoperative pain and to facilitate rehabilitation, but also to improve both the quality of the reconstruction and the functional outcome.

Autophagy-mediated NCOR1 degradation is required for brown fat maturation and thermogenesis.

Brown adipose tissue (BAT) thermogenesis affects energy balance, and thereby it has the potential to induce weight loss and to prevent obesity. Here, we document a macroautophagic/autophagic-dependent mechanism of peroxisome proliferator-activated receptor gamma (PPARG) activity regulation that induces brown adipose differentiation and thermogenesis and that is mediated by TP53INP2. Disruption of TP53INP2-dependent autophagy reduced brown adipogenesis in cultured cells. In vivo specific-tp53inp2 ablation in brown precursor cells or in adult mice decreased the expression of thermogenic and mature adipocyte genes in BAT. As a result, TP53INP2-deficient mice had reduced UCP1 content in BAT and impaired maximal thermogenic capacity, leading to lipid accumulation and to positive energy balance. Mechanistically, TP53INP2 stimulates PPARG activity and adipogenesis in brown adipose cells by promoting the autophagic degradation of NCOR1, a PPARG co-repressor. Moreover, the modulation of TP53INP2 expression in BAT and in human brown adipocytes suggests that this protein increases PPARG activity during metabolic activation of brown fat. In all, we have identified a novel molecular explanation for the contribution of autophagy to BAT energy metabolism that could facilitate the design of therapeutic strategies against obesity and its metabolic complications.

Simple beam hardening correction method (2DCalBH) based on 2D linearization.

Objective. The polychromatic nature of the x-ray spectrum in computed tomography leads to two types of artifacts in the reconstructed image: cupping in homogeneous areas and dark bands between dense parts, such as bones. This fact, together with the energy dependence of the mass attenuation coefficients of the tissues, results in erroneous values in the reconstructed image. Many post-processing correction schemes previously proposed require either knowledge of the x-ray spectrum or the heuristic selection of some parameters that have been shown to be suboptimal for correcting different slices in heterogeneous studies. In this study, we propose and validate a method to correct the beam hardening artifacts that avoids such restrictions and restores the quantitative character of the image.Approach. Our approach extends the idea of the water-linearization method. It uses a simple calibration phantom to characterize the attenuation for different soft tissue and bone combinations of the x-ray source polychromatic beam. The correction is based on the bone thickness traversed, obtained from a preliminary reconstruction. We evaluate the proposed method with simulations and real data using a phantom composed of PMMA and aluminum 6082 as materials equivalent to water and bone.Main results. Evaluation with simulated data showed a correction of the artifacts and a recovery of monochromatic values similar to that of the post-processing techniques used for comparison, while it outperformed them on real data.Significance. The proposed method corrects beam hardening artifacts and restores monochromatic attenuation values with no need of spectrum knowledge or heuristic parameter tuning, based on the previous acquisition of a very simple calibration phantom.

Tolerance to geometrical inaccuracies in CBCT systems: A comprehensive study.

PURPOSE: The last decades have seen the consolidation of the cone-beam CT (CBCT) technology, which is nowadays widely used for different applications such as micro-CT for small animals, mammography, dentistry, or surgical procedures. Some CBCT systems may suffer mechanical strains due to the heavy load of the x-ray tube. This fact, together with tolerances in the manufacturing process, lead to different types of undesirable effects in the reconstructed image unless they are properly accounted for during the reconstruction. To obtain good quality images, it is necessary to have a complete characterization of the system geometry including the angular position of the gantry, the source-object and detector-object distances, and the position and pose of the detector. These parameters can be obtained through a calibration process done periodically, depending on the stability of the system geometry. To the best of our knowledge, there are no comprehensive works studying the effect of inaccuracies in the geometrical calibration of CBCT systems in a systematic and quantitative way. In this work, we describe the effects of detector misalignments (linear shifts, rotation, and inclinations) on the image and define their tolerance as the maximum error that keeps the image free from artifacts. METHODS: We used simulations of four phantoms including systematic and random misalignments. Reconstructions of these data with and without errors were compared to identify the artifacts introduced in the reconstructed image and the tolerance to miscalibration deemed to provide acceptable image quality. RESULTS: Visual assessment provided an easy guideline to identify the sources of error by visual inspection of the artifactual images. Systematic errors result in blurring, shape distortion and/or reduction of the axial field of view while random errors produce streaks and blurring in all cases, with a tolerance which is more than twice that of systematic errors. The tolerance corresponding to errors in position of the detector along the tangential direction, that is, skew (<0.2°) and horizontal shift (<0.4 mm), is tighter than the tolerance to those errors affecting the position along the longitudinal direction or the magnification, that is, vertical shift (<2 mm), roll (<1.5°), tilt (<2°), and SDD (<3 mm). CONCLUSION: We present a comprehensive study, based on realistic simulations, of the effects on the reconstructed image quality of errors in the geometrical characterization of a CBCT system and define their tolerance. These results could be used to guide the design of new systems, establishing the mechanical precision that must be achieved, and to help in the definition of an optimal geometrical calibration process. Also, the thorough visual assessment may be valuable to identify the most predominant sources of error based on the effects shown in the reconstructed image.

Optimization of a calibration phantom for quantitative radiography.

OBJECTIVE: Dual energy radiography (DER) makes it possible to obtain separate images for soft-tissue and bony structures (tissue maps) based on the acquisition of two radiographs at different source peak-kilovoltage values. Current DER studies are based on the weighted subtraction method, which requires either manual tuning or the use of precomputed tables, or on decomposition methods, which make use of a calibration to model soft-tissue and bone components. In this study, we examined in depth the optimum method to perform this calibration. METHODS: We used simulations to optimize the calibration protocol and evaluated the effect of the material and size of a calibration phantom composed of two wedges and its positioning in the system. Evaluated materials were water, PMMA and A-150 as soft-tissue equivalent, and Teflon, B-100 and aluminum as bone equivalent, with sizes from 5 to 30 cm. Each material combination was compared with an ideal phantom composed of soft tissue and bone. Our simulation results enabled us to propose four designs that were tested with the NOVA FA X-ray system with a realistic thorax phantom. RESULTS: Calibration based on a very simple and inexpensive phantom with no strict requirements in its placement results in appropriate separation of the spine (a common focus in densitometry studies) and the identification of nodules as small as 6 mm, which have been reported to have a low rate of detection in radiography. CONCLUSION: The proposed method is completely automatic, avoiding the need for a radiology technician with expert knowledge of the protocol, as is the case in densitometry exams. The method provides real mass thickness values, enabling quantitative planar studies instead of relative comparisons.

Simplified Statistical Image Reconstruction for X-ray CT With Beam-Hardening Artifact Compensation.

CT images are often affected by beam-hardening artifacts due to the polychromatic nature of the X-ray spectra. These artifacts appear in the image as cupping in homogeneous areas and as dark bands between dense regions such as bones. This paper proposes a simplified statistical reconstruction method for X-ray CT based on Poisson statistics that accounts for the non-linearities caused by beam hardening. The main advantages of the proposed method over previous algorithms are that it avoids the preliminary segmentation step, which can be tricky, especially for low-dose scans, and it does not require knowledge of the whole source spectrum, which is often unknown. Each voxel attenuation is modeled as a mixture of bone and soft tissue by defining density-dependent tissue fractions and maintaining one unknown per voxel. We approximate the energy-dependent attenuation corresponding to different combinations of bone and soft tissues, the so-called beam-hardening function, with the 1D function corresponding to water plus two parameters that can be tuned empirically. Results on both simulated data with Poisson sinogram noise and two rodent studies acquired with the ARGUS/CT system showed a beam hardening reduction (both cupping and dark bands) similar to analytical reconstruction followed by post-processing techniques but with reduced noise and streaks in cases with a low number of projections, as expected for statistical image reconstruction.

Author Correction: Hsp70 and Hsp40 inhibit an inter-domain interaction necessary for transcriptional activity in the androgen receptor.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Hsp70 and Hsp40 inhibit an inter-domain interaction necessary for transcriptional activity in the androgen receptor.

Molecular chaperones such as Hsp40 and Hsp70 hold the androgen receptor (AR) in an inactive conformation. They are released in the presence of androgens, enabling transactivation and causing the receptor to become aggregation-prone. Here we show that these molecular chaperones recognize a region of the AR N-terminal domain (NTD), including a FQNLF motif, that interacts with the AR ligand-binding domain (LBD) upon activation. This suggests that competition between molecular chaperones and the LBD for the FQNLF motif regulates AR activation. We also show that, while the free NTD oligomerizes, binding to Hsp70 increases its solubility. Stabilizing the NTD-Hsp70 interaction with small molecules reduces AR aggregation and promotes its degradation in cellular and mouse models of the neuromuscular disorder spinal bulbar muscular atrophy. These results help resolve the mechanisms by which molecular chaperones regulate the balance between AR aggregation, activation and quality control.

Autophagy Exacerbates Muscle Wasting in Cancer Cachexia and Impairs Mitochondrial Function.

Cancer cachexia is a multifactorial syndrome characterized by anorexia, weight loss and muscle wasting that impairs patients' quality of life and survival. Aim of this work was to evaluate the impact of either autophagy inhibition (knocking down beclin-1) or promotion (overexpressing TP53INP2/DOR) on cancer-induced muscle wasting. In C26 tumor-bearing mice, stress-induced autophagy inhibition was unable to rescue the loss of muscle mass and worsened muscle morphology. Treating C26-bearing mice with formoterol, a selective ß2-agonist, muscle sparing was paralleled by reduced static autophagy markers, although the flux was maintained. Conversely, the stimulation of muscle autophagy exacerbated muscle atrophy in tumor-bearing mice. TP53INP2 further promoted atrogene expression and suppressed mitochondrial dynamics-related genes. Excessive autophagy might impair mitochondrial function through mitophagy. Consistently, tumor-induced mitochondrial dysfunction was detected by reduced ex vivo muscle fiber respiration. Overall, the results evoke a central role for muscle autophagy in cancer-induced muscle wasting.

Regulation of Androgen Receptor Activity by Transient Interactions of Its Transactivation Domain with General Transcription Regulators.

The androgen receptor is a transcription factor that plays a key role in the development of prostate cancer, and its interactions with general transcription regulators are therefore of potential therapeutic interest. The mechanistic basis of these interactions is poorly understood due to the intrinsically disordered nature of the transactivation domain of the androgen receptor and the generally transient nature of the protein-protein interactions that trigger transcription. Here, we identify a motif of the transactivation domain that contributes to transcriptional activity by recruiting the C-terminal domain of subunit 1 of the general transcription regulator TFIIF. These findings provide molecular insights into the regulation of androgen receptor function and suggest strategies for treating castration-resistant prostate cancer.

Bactofection of sequences encoding a Bax protein peptide chemosensitizes prostate cancer tumor cells / Bactofección de secuencias que codifican para un péptido de la proteína Bax quimiosensibiliza a células tumorales de cáncer de próstata

Abstract: Background: Tumor cell resistance to chemotherapy agents is one of the main problems in the eradication of different neoplasias. One of the mechanisms of this process is the overexpression of anti-apoptotic proteins such as Bcl-2 and Bcl-XL; blocking the activity of these proteins may contribute to the sensitization of tumor cells and allow the adequate effects of chemotherapeutic drugs. Methods and results: This study adressed the transfection of prostate cancer cells (PC3) with a plasmid encoding a recombinant protein with an antagonist peptide from the BH3 region of the Bax protein fused to the GFP reporter protein (BaxGFP). This protein induced apoptosis of these tumor cells; further, selective transport of this plasmid to the tumor cell with Salmonella enterica serovar Typhimurium (strain SL3261), a live-attenuated bacterial vector, can induce sensitization of the tumor cell to the action of drugs such as cisplatin, through a process known as bactofection. Conclusions: These results suggest that Salmonella enterica can be used as a carrier vector of nucleotide sequences encoding heterologous molecules used in antitumor therapy.

Resumen: Introducción: La resistencia a los agentes quimioterapéuticos por parte de las células tumorales es uno de los principales problemas para la erradicación de distintas neoplasias. Uno de los mecanismos involucrados en este proceso es la sobreexpresión de proteínas antiapoptóticas como Bcl-2 y Bcl-XL. El bloquear la actividad de estas proteínas puede contribuir a la sensibilización de las células tumorales, permitiendo que los fármacos quimioterapeúticos funcionen de forma adecuada. Métodos y resultados: En este trabajo se llevó a cabo la transfección de células de cáncer de próstata (PC3) por un plásmido que codifica para una proteína recombinante que contiene un péptido antagónico perteneciente a la región BH3 de la proteína Bax fusionada a la proteína reportera GFP (BaxGFP). Esta proteína fue capaz de inducir apoptosis en las células PC3. El transporte selectivo de este plásmido hacia la célula tumoral empleando Salmonella enterica serovar Typhimurium cepa SL3261, un vector bacteriano vivo atenuado, permitió la sensibilización de la célula tumoral a la acción de fármacos como el cisplatino mediante un proceso denominado bactofección. Conclusiones: Estos resultados sugieren que Salmonella enterica puede emplearse como un vector acarreador de secuencias nucleotídicas que codifican para moléculas heterólogas empleadas en la terapia antitumoral.

RENACER study: Assessment of 12-month efficacy and safety of 168 certolizumab PEGol rheumatoid arthritis-treated patients from a Spanish multicenter national database.

OBJECTIVE: To assess effectiveness and safety of certolizumab PEGol (CZP) in rheumatoid arthritis (RA) patients after 12 months of treatment and to detect predictors of response. METHODS: Observational longitudinal prospective study of RA patients from 35 sites in Spain. Variables (baseline, 3- and 12-month assessment): sociodemographics, previous Disease Modifying Anti-Rheumatic Drug (DMARD) and previous Biological Therapies (BT) use; TJC, SJC, ESR, CRP, DAS28, SDAI. Response variables: TJC, SJC, CRP, ESR, and steroids dose reductions, EULAR Moderate/Good Response, SDAI response and remission, DAS28 remission. Safety variables: discontinuation due to side-effects. Descriptive, comparative and Logistic regression analyses were performed. RESULTS: We included 168 patients: 79.2% women, mean age 54.5 years (±13.2 SD), mean disease duration 7.5 years (±7.3 SD). Mean number of prior DMARD: 1.4 (±1.2 SD), mean number of prior BT was 0.8 (±1.1). Mean time on CZP was 9.8 months (±3.4 SD). A total of 71.4% were receiving CZP at 12-month assessment. Baseline predictors of response: lower prior number DMARD; low number prior BT; higher CRP, ESR, TJC, SJC, DAS28 and SDAI (p < 0.05) scores. A 25/46.4% Moderate/Good Response, a 20% SDAI remission, and a 44% DAS28 remission were observed. We observed 48 discontinuations (28.6%), 31 due to partial or complete ineffectiveness, and 17 due to side-effects. CONCLUSIONS: CZP showed benefit in severe RA patients, with significant reduction of all effectiveness parameters, despite the high prevalence of previous BT exposure in our series. We found CRP, ESR, prior DMARD/BT number, TJC, SJC, DAS28, and SDAI as baseline predictors of response. CZP was mostly well tolerated.

Bactofection of sequences encoding a Bax protein peptide chemosensitizes prostate cancer tumor cells.

BACKGROUND: Tumor cell resistance to chemotherapy agents is one of the main problems in the eradication of different neoplasias. One of the mechanisms of this process is the overexpression of anti-apoptotic proteins such as Bcl-2 and Bcl-XL; blocking the activity of these proteins may contribute to the sensitization of tumor cells and allow the adequate effects of chemotherapeutic drugs. METHODS AND RESULTS: This study adressed the transfection of prostate cancer cells (PC3) with a plasmid encoding a recombinant protein with an antagonist peptide from the BH3 region of the Bax protein fused to the GFP reporter protein (BaxGFP). This protein induced apoptosis of these tumor cells; further, selective transport of this plasmid to the tumor cell with Salmonella enterica serovar Typhimurium (strain SL3261), a live-attenuated bacterial vector, can induce sensitization of the tumor cell to the action of drugs such as cisplatin, through a process known as bactofection. CONCLUSIONS: These results suggest that Salmonella enterica can be used as a carrier vector of nucleotide sequences encoding heterologous molecules used in antitumor therapy.