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Abstract Resistance to aromatase inhibitor (AI) treatment and combined CDK4/6 inhibitor (CDK4/6i) and endocrine therapy (ET) are crucial clinical challenges in treating estrogen receptor-positive (ER+) breast cancer. Understanding the resistance mechanisms and identifying reliable predictive biomarkers and novel treatment combinations to overcome resistance are urgently needed. Herein, we show that upregulation of CDK6, p-CDK2, and/or cyclin E1 is associated with adaptation and resistance to AI-monotherapy and combined CDK4/6i and ET in ER+ advanced breast cancer. Importantly, co-targeting CDK2 and CDK4/6 with ET synergistically impairs cellular growth, induces cell cycle arrest and apoptosis, and delays progression in AI-resistant and combined CDK4/6i and fulvestrant-resistant cell models and in an AI-resistant autocrine breast tumor in a postmenopausal xenograft model. Analysis of CDK6, p-CDK2, and/or cyclin E1 expression as a combined biomarker in metastatic lesions of ER+ advanced breast cancer patients treated with AI-monotherapy or combined CDK4/6i and ET revealed a correlation between high biomarker expression and shorter progression-free survival (PFS), and the biomarker combination was an independent prognostic factor in both patients cohorts. Our study supports the clinical development of therapeutic strategies co-targeting ER, CDK4/6 and CDK2 following progression on AI-monotherapy or combined CDK4/6i and ET to improve survival of patients exhibiting high tumor levels of CDK6, p-CDK2, and/or cyclin E1.

La esencia de la Medicina es el servicio al ser humano, y su enseñanza se realiza por medio del método clínico y un conjunto de habilidades que el estudiante debe adquirir durante toda su formación. Sin embargo, es posible que haya un problema pedagógico en el modelo actual que hace que los médicos y estudiantes se sientan insatisfechos con su proceso académico, repercutiendo en su vida profesional. El propósito de esta revisión es dar a conocer algunos aspectos que se viven como estudiante de Medicina en Colombia, las implicaciones que ha tenido el uso de la tecnología en la formación médica, y su repercusión en la vida laboral y académica.

Synechocystis sp. PCC 6803 is a widely used model cyanobacterium whose genome has been well annotated. However, several additional small protein coding sequences (sORFs) have been recently identified, which might play important roles, for example in the regulation of cellular metabolism. Here, we analyzed the function of a sORF encoding a 44 amino acid peptide showing high similarity to the N-terminal part of aconitase (AcnB). The expression of the gene, which probably originated from a partial gene duplication of chromosomal acnB into the plasmid pSYSA, was verified and it was designated as acnSP. The protein-coding part of acnSP was inactivated by interposon mutagenesis. The obtained mutant displayed slower growth under photoautotrophic conditions with light exceeding 100 μmol photons m–2 s–1 and showed significant changes in the metabolome compared to wild type, including alterations in many metabolites associated to the tricarboxylic acid (TCA) cycle. To analyze a possible direct impact of AcnSP on aconitase, the recombinant Synechocystis enzyme was generated and biochemically characterized. Biochemical analysis revealed that addition of equimolar amounts of AcnSP resulted in an improved substrate affinity (lower Km) and lowered Vmax of aconitase. These results imply that AcnSP can regulate aconitase activity, thereby impacting the carbon flow into the oxidative branch of the cyanobacterial TCA cycle, which is mainly responsible for the synthesis of carbon skeletons needed for ammonia assimilation.

Abstract Cyanobacteria is a remarkable group of prokaryotic photosynthetic microorganisms, with several genera capable of fixing atmospheric nitrogen (N2) and presenting a wide range of morphologies. Although the nitrogenase complex is not present in all cyanobacterial taxa, it is spread across several cyanobacterial strains. The nitrogenase complex has also a high theoretical potential for biofuel production, since H2 is a by-product produced during N2 fixation. In this review we discuss the significance of a relatively wide variety of cell morphologies and metabolic strategies that allow spatial and temporal separation of N2 fixation from photosynthesis in cyanobacteria. Phylogenetic reconstructions based on 16S rRNA and nifD gene sequences shed light on the evolutionary history of the two genes. Our results demonstrated that (i) sequences of genes involved in nitrogen fixation (nifD) from several morphologically distinct strains of cyanobacteria are grouped in similarity with their morphology classification and phylogeny, and (ii) nifD genes from heterocytous strains share a common ancestor. By using this data we also discuss the evolutionary importance of processes such as horizontal gene transfer and genetic duplication for nitrogenase evolution and diversification. Finally, we discuss the importance of H2 synthesis in cyanobacteria, as well as strategies and challenges to improve cyanobacterial H2 production.

Background: Transcranial direct current stimulation (tDCS), a non-invasive brain stimulation technique, has been studied as an adjunctive therapeutic agent for alcohol dependence. In a previous study, we showed that five consecutive sessions of tDCS applied bilaterally over the dorsolateral prefrontal cortex (dlPFC) reduced relapse to the use of alcohol in alcohol use disorder (AUD) outpatients. However, no changes on craving scores were observed. In the present study, we investigated if an extended number of sessions of the same intervention would reduce craving and relapses for alcohol use in AUD inpatients.Methods: Thus, a randomized, double-blind, sham-controlled, clinical trial with parallel arms was conducted (https://clinicaltrials.gov/ct2/show/NCT02091284). AUD patients from two private and one public clinics for treatment of drug dependence were randomly allocated to two groups: real tDCS (5 × 7 cm2, 2 mA, for 20 min, cathodal over the left dlPFC, and anodal over the right dlPFC) and sham-tDCS. Real or sham-tDCS was applied once a day, every other day, in a total of 10 sessions. Craving was monitored by a 5-item obsessive compulsive drinking scale once a week (one time before, three times during and once after brain stimulation) over about 5 weeks.Results: Craving scores progressively decreased over five measurements in both groups but were significantly reduced only in the real tDCS group after treatment. Corrected Hedges' within-group (initial and final) effect sizes of craving scores were of 0.3 for the sham-tDCS and of 1.1 for the real tDCS group. Effect size was 3-fold larger in the real tDCS group. In addition, the between-group analysis on craving score difference was nearly significant, and the effect size was 0.58, in favor for a larger effect in the real tDCS group when compared to sham-tDCS. Furthermore, in a 3-months follow-up after intervention, 72.2% of sham-tDCS group relapsed to the alcohol use whereas 72.7% of tDCS group were abstinent.Conclusions: Multiple sessions of bilateral prefrontal tDCS were well tolerated with no significant adverse events. Thus, extended repetitive bilateral tDCS over the dlPFC is a promising adjunctive clinical tool that could be used to reduce alcohol craving and relapses and facilitate alcoholism cessation.

La presente entrevista es una invitación a repensar el estado actual del periodismo ecuatoriano, visto desde una perspectiva que revela la crisis profunda en términos de ética y representación que atraviesa, debido al enfoque caracterizado por la fijación, priorización y jerarquización de la agenda mediática y una actitud que podría tildarse de indecente en la aplicación de estrategias de abordaje, o en su defecto, ocultamiento de ciertos acontecimientos de la realidad, haciendo de las dinámicas de poder, el núcleo central del criterio de noticiabilidad que utilizan los medios de comunicación comerciales del Ecuador. Este extravío deontológico ha desviado la atención del propósito del periodismo, que de acuerdo con la postura de Cerbino, consiste en revelar lo ordinario, acercar lo lejano y familiarizar lo desconocido o poco comprendido, para ponerlo al servicio de la ciudadanía, a fin de facultarla para formar su propio juicio sobre la realidad.

Abstract Older adults in disaster contexts are often thought of as a passive, vulnerable population that lacks agency and capacities to cope in the aftermath. However, it can be argued that older adults may have underrecognized strengths that can be utilized pre-, peri-, and post-disaster. One of these strengths is older adults’ unique social capital that stems from long-standing connections with other members of their respective communities. Using data from in-depth, semistructured interviews with farmers in British Columbia 3–11 months after the 2021 floods, this research explored the experiences of older adult farmers’ recovery. The farmers discussed how they leveraged their social capital to aid in their recovery efforts from the flood event. By using their bonding social capital, older adult farmers transformed their existing, deep-rooted connections into post-disaster assistance. This, in turn, generated the idea of the therapeutic community, helping community members cope in the aftermath. This research indicated the need to further examine how older adults in disaster settings can be viewed as assets with community knowledge and skills as opposed to solely as a vulnerable population.

Homelessness in psychiatric patients in Flanders, Belgium, has never been investigated. Advocacy groups from patients with lived experience of psychiatric disorders have sounded the alarm on the scarcity of suitable housing options, the strain on psychiatric institutions, and the challenges faced by social service workers. To investigate the extent of the problem a survey on the topic was initiated. A “homelessness-in-mental-health-questionnaire” was designed by experts in the field. The social services of all Flemish psychiatric hospitals and all psychiatric wards in general hospitals were contacted and invited to complete this survey. 24 of 70 contacted services responded. The total number of homeless patients in the inpatient setting on an annual basis are estimated to an average 19.5%. 18% of homeless patients remain longer in admission due to the lack of housing options. 13.7% of homeless psychiatric patients are referred to a community care facility such as an assisted living facility. Social service respondents reported spending an average of 27.4% of their work time on housing issues. The main focus points according to the respondents are the lack of priority measures for homeless psychiatric patients, psychiatric problems as a barrier to housing options and the shortage of adapted housing capacity. The conclusion of this study is the need for comprehensive policy interventions to ensure an adequate supply of suitable social housing for psychiatric patients, accessible mental health care, alternative housing options and crisis accommodation facilities. We propose a 10-point action plan on housing for psychiatric patients for policymakers and politicians.

The escalating environmental impact of plastic packaging waste necessitates sustainable alternatives in food packaging. This study explores starch-based films derived from cassava and potato as viable substitutes, aiming to mitigate plastic pollution and enhance environmental sustainability. Utilizing a casting method, formulations optimized by CCRD were characterized for their physical, physicochemical, and morphological properties. Comprehensive analysis revealed both cassava and potato starch films to exhibit robust structural integrity, high tensile strength (up to 32.6 MPa for cassava starch films), and semi-crystalline morphology. These films demonstrated low water vapor permeability and moderate solubility, akin to conventional low-density polyethylene used in packaging. Differential scanning calorimetry indicated glass transition temperatures between 116.36 °C and 119.35 °C, affirming thermal stability suitable for packaging applications. Scanning electron microscopy confirmed homogeneous film surfaces, with cassava starch films (C4-15) exhibiting superior transparency and uniformity. X-ray diffraction corroborated the films’ semi-crystalline nature, unaffected by sorbitol content variations. Despite their mechanical and thermal suitability, further enhancements in thermal degradation resistance are essential for broader thermoprocessing applicability. These findings underscore the potential of starch-based films to be used as lids or other part of a food package, decreasing the plastic dependency in food packaging, contributing decisively to waste reduction and environmental preservation.

Background: Upfront cytoreductive nephrectomy (CN) is no longer the standard of care for patients with metastastic renal cell carcinoma (mRCC) with intermediate or poor prognosis according to the International mRCC Database Consortium categories. Objective: To investigate indications for CN following first-line ipilimumab-nivolumab, and assess management and outcomes for patients achieving no evidence of disease (NED) after CN. Design, setting, and participants: This was a retrospective cohort study among 125 patients with synchronous mRCC who received ipilimumab-nivolumab treatment between March 2019 and June 2022 at four European centres. At one of the four centres, nivolumab was stopped following NED. Outcome measurements and statistical analysis: We measured complete response of metastases (mCR) according to Response Evaluation Criteria in Solid Tumours 1.1; near-complete response of mestastases (mnCR) was defined as a >80% reduction in cumulative metastatic volume. Treatment-free survival (TFS), disease-free survival (DFS), progression-free survival (PFS), and cancer-specific survival (CSS) were determined. Results and limitations: At median follow-up of 25 mo, 23/125 patients (18%) had undergone deferred CN. Of 26 patients (21%) with mCR or mnCR, 19 (73%) underwent CN to achieve NED, of whom 11 (58%) discontinued nivolumab, with median TFS of 21 mo. For patients who continued (n = 8, 42%) versus discontinued nivolumab following NED, 2-yr DFS was 83% versus 60% (p = 0.675) and 3-yr CSS was 100% versus 70% (p = 0.325). Four patients underwent CN because of a dissociated response of the primary tumour and were still alive at median follow-up of 5 mo. Conclusions: CN can result in NED, durable DFS, and substantial time off systemic therapy. More collaborative data are required to ascertain the benefits of treatment discontinuation versus oncologic safety. Patient summary: In our study using real-world data, 18% of patients treated with immunotherapy underwent deferred kidney surgery. The majority were free of disease after 3 years. Half of the patients who stopped immunotherapy after surgery have been off therapy for 21 months or longer. Larger studies are needed to investigate the effect of kidney surgery and discontinuation of immunotherapy on survival.

OBJECTIVE: Periprosthetic femoral fractures (PFF) are a serious complication in patients who have undergone hip arthroplasty. Some authors consider revision arthroplasty as the gold standard in the surgical treatment of Vancouver type B2 and B3 PFF. Others, however, prefer treating PFF by open reduction and internal fixation (ORIF), without revising loose stems, especially in elderly patients. In the present retrospective study, we report mid/long-term results in a series of patients affected by B2 or B3 PFF surgically treated by ORIF, using a locking compression plate (LCP), thus avoiding the need of revision arthroplasty. MATERIALS AND METHODS: We reviewed 28 patients affected by B2 or B3 PFF surgically treated between 2010 and 2017 by ORIF using a LCP, after an average follow-up of 5.5 years. The average age of the patients at diagnosis was 78 years; in 17 patients, the femoral stem was uncemented while in 11, cemented. The mean interval time between hip arthroplasty and PFF was 6.7 years. Clinical results were assessed using Harris Hip Score (HHS), while radiographic results according to Beals and Tower criteria. RESULTS: At follow-up, HHS ranged from 72 to 96 points; 8 patients had an excellent result, 12 got a good result and 8 a fair result. According to Beals and Tower criteria, all the radiographic results were excellent (9 patients) or good (19 patients). The majority of our patients returned to their previous ambulatory levels. CONCLUSIONS: According to our results, in elderly patients affected by Vancouver type B2 or B3 PFF, surgical treatment by ORIF using a locking compression plate, without a stem revision, seems to be associated with satisfactory outcome. [ABSTRACT FROM AUTHOR]

Acute limb ischemia due to limb-graft occlusion (LGO) after fenestrated endovascular aneurysm repair (FEVAR) and acute bypass graft occlusion with an ePTFE graft pose critical challenges, necessitating prompt intervention to prevent limb loss. This paper discusses two cases of acute limb ischemia treated with a hybrid approach using the AngioJet™ Ultra Thrombectomy System as an adjunct to Fogarty thrombectomy. Case I involved a 69-year-old male post-FEVAR with contralateral iliac limb graft occlusion of the fenestrated Anaconda™, while Case II featured a 70-year-old male (ASA IV) post-bypass surgery (iliopopliteal arterial bypass with ePTFE Graft) with acute bypass graft occlusion. Both cases underwent successful recanalization using the AngioJet™ Ultra Thrombectomy System (ZelanteDVT™ 8F catheter, Solent™ Proxi 6F catheter) (Boston Scientific, Marlborough, MA, USA), combined with adjunctive techniques including Fogarty thrombectomy, balloon angioplasty, stenting, and local lysis. Immediate postoperative and follow-up assessments after 6 months revealed restored limb perfusion and improved clinical outcomes, with palpable pulses and improved ulcer healing. The aim of this treatment strategy is not only to alleviate limb ischemia but also to preserve future options in the event of graft failure. The use of the AngioJet™ Thrombectomy System in cases of LGO aims not only to clear the thrombus load but also to avoid the need for graft relining. In the case of acute arterial bypass graft occlusion in a patient with ASA IV, the goal of using the thrombectomy device is to preserve the native vessels for future procedures, such as long infragenual bypass, in addition to limb salvage. These cases demonstrate the efficacy of a hybrid surgical approach in managing acute limb ischemia following graft occlusion following FEVAR and bypass surgery. Long-term follow-up will further elucidate the durability of these interventions and their impact on limb salvage and overall patient outcomes. By combining mechanical thrombectomy with adjunctive techniques, such as balloon angioplasty and stenting, this hybrid approach offers a comprehensive solution to acute limb ischemia, addressing both the underlying occlusive pathology and ensuring optimal limb perfusion. Furthermore, the utilization of the AngioJet™ Ultra Thrombectomy System provides a minimally invasive yet effective method for thrombus removal, reducing procedural time and potential complications associated with open surgical techniques. As such, this approach represents a valuable addition to the armamentarium of treatments for acute limb ischemia, particularly in cases of graft occlusion following complex endovascular and bypass procedures.

The role of abscisic acid (ABA) was analyzed in roots and leaves of the halophyte Prosopis strombulifera in response to low osmotic potential (Ψo: −1.0, −1.9, and −2.6 MPa) induced by sodium chloride (NaCl), sodium sulfate (Na2SO4), and the iso-osmotic combination of both compounds (NaCl + Na2SO4). P. strombulifera plants were sprayed with ABA, as well as with inhibitors of ABA biosynthesis (sodium tungstate and fluridone). Different parameters were measured, including total plant height, leaf number, root length, root and shoot biomass, water content, transpiration rate, and total soluble carbohydrates, specific carbohydrates and ABA concentrations. Results showed that sodium salts affected growth parameters in varying ways, depending on the type of salts used as well as the osmotic potentials. ABA-sprayed plants displayed the lowest transpiration values. These plants had a higher content of total soluble carbohydrates in roots, greater root biomass and length and increased root/shoot rate. This study shows that ABA triggers different biochemical and physiological responses after the perception of a stressful condition, and that the interaction between different concentrations and types of salts, and the addition of ABA or its inhibitors generates responses that affect development and growth in the halophyte P. strombulifera. [ABSTRACT FROM AUTHOR]