The Effect of Adverse Surgical Margins on the Risk of Biochemical Recurrence after Robotic-Assisted Radical Prostatectomy

Positive surgical margins (PSM) after radical prostatectomy are associated with a greater risk of biochemical recurrence (BCR). However, not all PSM harbour the same prognosis for recurrence. We aim to determine the impact of different PSM characteristics and their coexistence on the risk of BCR. This retrospective study included 333 patients that underwent robotic-assisted radical prostatectomy for prostate cancer between 2015-2020 at a single institution. The effect of PSM and their adverse characteristics on the risk of BCR was assessed using Cox proportional hazard models. Kaplan-Meier was used to represent BCR-free survival stratified by margin status. With a median follow-up of 34.5 months, patients with PSM had a higher incidence of BCR, higher risk of relapse and lower BCR-free survival than negative margins (p < 0.001). We established as adverse characteristics: PSM length ≥ 3 mm, multifocality and Gleason at margin > 3. PSM ≥ 3 mm or multifocal PSM were associated with an increased risk for BCR compared to favourable margins (HR 3.50; 95% CI 2.05-5.95, p < 0.001 and HR 2.18; 95% CI 1.09-4.37, p = 0.028, respectively). The coexistence of these two adverse features in the PSM also conferred a higher risk for biochemical relapse and lower BCR-free survival. Adverse Gleason in the margin did not confer a higher risk for BCR than non-adverse margins in our models. We concluded that PSM are an independent predictor for BCR and that the presence of adverse characteristics, such as length and focality, and their coexistence in the PSM are associated with a greater risk of recurrence. Nevertheless, subclassifying PSM with adverse features did not enhance the model's predictive performance in our cohort

Consensus document on allergic conjunctivitis (DECA)

Allergic conjunctivitis (AC) is an inflammatory disease of the conjunctiva caused mainly by an IgE-mediated mechanism. It is the most common type of ocular allergy. Despite being the most benign form of conjunctivitis, AC has a considerable effect on patient quality of life, reduces work productivity, and increases health care costs. No consensus has been reached on its classification, diagnosis, or treatment. Consequently, the literature provides little information on its natural history, epidemiological data are scarce, and it is often difficult to ascertain its true morbidity. The main objective of the Consensus Document on Allergic Conjunctivitis (Documento dE Consenso sobre Conjuntivitis Alérgica [DECA]), which was drafted by an expert panel from the Spanish Society of Allergology and Spanish Society of Ophthalmology, was to reach agreement on basic criteria that could prove useful for both specialists and primary care physicians and facilitate the diagnosis, classification, and treatment of AC. This document is the first of its kind to describe and analyze aspects of AC that could make it possible to control symptoms

Senescence plays a role in myotonic dystrophy type 1 br

Myotonic dystrophy type 1 (DM1; MIM #160900) is an autosomal dominant disorder, clinically characterized by progressive muscular weakness and multisystem degeneration. The broad phenotypes observed in patients with DM1 resemble the appearance of an accelerated aging process. However, the molecular mechanisms underlying these phenotypes remain largely unknown. Transcriptomic analysis of fibroblasts derived from patients with DM1 and healthy individuals revealed a decrease in cell cycle activity, cell division, and DNA damage response in DM1, all of which related to the accumulation of cellular senescence. The data from transcriptome analyses were corroborated in human myoblasts and blood samples, as well as in mouse and Drosophila models of the disease. Serial passage studies in vitro confirmed the accelerated increase in senescence and the acquisition of a senescence-associated secretory phenotype in DM1 fibroblasts, whereas the DM1 Drosophila model showed reduced longevity and impaired locomotor activity. Moreover, functional studies highlighted the impact of BMI1 and downstream p16INK4A/ RB and ARF/p53/p21CIP pathways in DM1-associated cellular phenotypes. Importantly, treatment with the senolytic compounds Quercetin, Dasatinib, or Navitoclax reversed the accelerated aging phenotypes in both DM1 fibroblasts in vitro and in Drosophila in vivo. Our results identify the accumulation of senescence as part of DM1 pathophysiology and, therefore, demonstrate the efficacy of senolytic compounds in the preclinical setting.MGP and ASA are recipient of predoctoral fellowships from the University of the Basque Country (PIF 15/245) and Carlos III Institute (FI17/00250), respectively. We thank the methodological support service of Biodonostia Institute for help with statistical analysis. This work is supported by grants from the Instituto Salud Carlos III and FEDER funds (PI16/01580, PI17/01841, DTS18/00181, PI19/01355, CPII19/00021, and DTS20/00179), La Caixa, and Health department from Basque Country (2017222021, 2018222021, and 2020333008)

Successful desensitization with human insulin in a patient with an insulin allergy and hypersensitivity to protamine: a case report

<p>Abstract</p> <p>Introduction</p> <p>Insulin allergy may occur in patients treated with subcutaneous applications of insulin preparations. Besides additives in the insulin preparation such as protamine, cresol, and phenol, the insulin molecule itself may be the cause of the allergy. In the latter case, therapeutic options are rare.</p> <p>Case presentation</p> <p>A 68-year-old man with poorly controlled type 2 diabetes mellitus received different insulin preparations subcutaneously while on oral medication. Six to eight hours after each subcutaneous application, he developed pruritic plaques with a diameter of >15 cm at the injection sites that persisted for several days. Allergologic testing revealed positive reactions against every insulin preparation and against protamine. Investigation of serum samples demonstrated IgG antibodies against human and porcine insulin. We treated the patient with human insulin using an ultra-rush protocol beginning with 0.004 IU and a rapid augmentation in dose up to 5 IU. Therapy was accompanied by antihistamine therapy. Subsequent conversion to therapy with glargine insulin (6 IE twice daily) was well-tolerated.</p> <p>Conclusion</p> <p>As reported in this case, desensitization with subcutaneously administered human insulin using an ultra-rush protocol in patients with an insulin allergy may present an easy form of therapy that is successful within a few days.</p

SIRT1 Undergoes Alternative Splicing in a Novel Auto-Regulatory Loop with p53

Background: The NAD-dependent deacetylase SIRT1 is a nutrient-sensitive coordinator of stress-tolerance, multiple homeostatic processes and healthspan, while p53 is a stress-responsive transcription factor and our paramount tumour suppressor. Thus, SIRT1-mediated inhibition of p53 has been identified as a key node in the common biology of cancer, metabolism, development and ageing. However, precisely how SIRT1 integrates such diverse processes remains to be elucidated. Methodology/Principal Findings: Here we report that SIRT1 is alternatively spliced in mammals, generating a novel SIRT1 isoform: SIRT1-DExon8. We show that SIRT1-DExon8 is expressed widely throughout normal human and mouse tissues, suggesting evolutionary conservation and critical function. Further studies demonstrate that the SIRT1-DExon8 isoform retains minimal deacetylase activity and exhibits distinct stress sensitivity, RNA/protein stability, and protein-protein interactions compared to classical SIRT1-Full-Length (SIRT1-FL). We also identify an auto-regulatory loop whereby SIRT1-DExon8 can regulate p53, while in reciprocal p53 can influence SIRT1 splice variation. Conclusions/Significance: We characterize the first alternative isoform of SIRT1 and demonstrate its evolutionary conservation in mammalian tissues. The results also reveal a new level of inter-dependency between p53 and SIRT1, two master regulators of multiple phenomena. Thus, previously-attributed SIRT1 functions may in fact be distributed betwee