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Ribosomal biogenesis and protein synthesis are deregulated in most cancers, suggesting that interfering with translation machinery may hold significant therapeutic potential. Here, we show that loss of the tumor suppressor adenomatous polyposis coli (APC), which constitutes the initiating event in the adenoma carcinoma sequence for colorectal cancer (CRC), induces the expression of RNA polymerase I (RNAPOL1) transcription machinery, and subsequently upregulates ribosomal DNA (rDNA) transcription. Targeting RNAPOL1 with a specific inhibitor, CX5461, disrupts nucleolar integrity, and induces a disbalance of ribosomal proteins. Surprisingly, CX5461‐induced growth arrest is irreversible and exhibits features of senescence and terminal differentiation. Mechanistically, CX5461 promotes differentiation in an MYC‐interacting zinc‐finger protein 1 (MIZ1)‐ and retinoblastoma protein (Rb)‐dependent manner. In addition, the inhibition of RNAPOL1 renders CRC cells vulnerable towards senolytic agents. We validated this therapeutic effect of CX5461 in murine‐ and patient‐derived organoids, and in a xenograft mouse model. These results show that targeting ribosomal biogenesis together with targeting the consecutive, senescent phenotype using approved drugs is a new therapeutic approach, which can rapidly be transferred from bench to bedside.

Cancers utilize sugar residues such as sialic acids (Sia) to improve their ability to survive. Sia presents a variety of functional group alterations, including O-acetylation on the C6 hydroxylated tail. Previously, sialylation has been reported to suppress EGFR activation and increase cancer cell sensitivity to Tyrosine Kinase Inhibitors (TKIs). In this study, we report on the effect of deacetylated Sia on the activity of three novel EGFR-targeting Cucurbitacin-inspired estrone analogs (CIEAs), MMA 294, MMA 321, and MMA 320, in lung and colon cancer cells. Acetylation was modulated by the removal of Sialate O-Acetyltransferase, also known as CAS1 Domain-containing protein (CASD1) gene via CRISPR-Cas9 gene editing. Using a variety of cell-based approaches including MTT cell viability assay, flow cytometry, immunofluorescence assay and in-cell ELISA we observed that deacetylated Sia-expressing knockout cells (1.24–6.49 μM) were highly sensitive to all CIEAs compared with the control cells (8.82–20.97 μM). Apoptosis and varied stage cell cycle arrest (G0/G1 and G2/M) were elucidated as mechanistic modes of action of the CIEAs. Further studies implicated overexpression of CIEAs’ cognate protein target, phosphorylated EGFR, in the chemosensitivity of the deacetylated Sia-expressing knockout cells. This observation correlated with significantly decreased levels of key downstream proteins (phosphorylated ERK and mTOR) of the EGFR pathway in knockout cells compared with controls when treated with CIEAs. Collectively, our findings indicate that Sia deacetylation renders lung and colon cancer cells susceptible to EGFR therapeutics and provide insights for future therapeutic interventions.

Macroautophagy (hereafter referred to as autophagy) is a homeostatic process that preserves cellular integrity. In mice, autophagy regulates pancreatic ductal adenocarcinoma (PDAC) development in a manner dependent on the status of the tumor suppressor gene Trp53. Studies published so far have investigated the impact of autophagy blockage in tumors arising from Trp53-hemizygous or -homozygous tissue. In contrast, in human PDACs the tumor suppressor gene TP53 is mutated rather than allelically lost, and TP53 mutants retain pathobiological functions that differ from complete allelic loss. In order to better represent the patient situation, we have investigated PDAC development in a well-characterized genetically engineered mouse model (GEMM) of PDAC with mutant Trp53 (Trp53R172H) and deletion of the essential autophagy gene Atg7. Autophagy blockage reduced PDAC incidence but had no impact on survival time in the subset of animals that formed a tumor. In the absence of Atg7, non-tumor-bearing mice reached a similar age as animals with malignant disease. However, the architecture of autophagy-deficient, tumor-free pancreata was effaced, normal acinar tissue was largely replaced with low-grade pancreatic intraepithelial neoplasias (PanINs) and insulin expressing islet β-cells were reduced. Our data add further complexity to the interplay between Atg7 inhibition and Trp53 status in tumorigenesis.

Objectives: The main objectives of this article are to systematically review the recent literature on patient safety in relation to the use of eHealth and to investigate how the Danish authorities supervise private eHealth clinics with regard to patient safety. Methods: Original studies reporting the association between patient safety and the use of eHealth as a means of communication between patients and healthcare providers were included. Four literature databases were searched for English-language articles reporting results from cohort studies and clinical trials, published from 2015 until March 2021. Moreover, registered private eHealth clinics in Denmark were evaluated with reference to a recent national audit of patient safety issues in eHealth. Results: The literature search retrieved four intervention studies. The studies did not identify any particular patient safety risks associated with the use of eHealth. Many different authorized healthcare providers (preferably, doctors) apply eHealth in various contexts. eHealth is being used as the only form of contact between the healthcare provider and the patient, as a supplement to patient visitations in an outpatient clinic, or as a tool for communicating between two or more healthcare providers. The regulation of eHealth involves patient safety issues but also has interfaces to marketing, IT systems, and infrastructure. Supervision of eHealth includes the organization of clinics, handling patient charts, prescription medicine, patient legal rights, and patient transition. However, there are many interfaces in the division of responsibilities among the various governmental players. Conclusion: eHealth is being used increasingly and in many settings, although recently published intervention studies investigating patient safety issues by the use of eHealth are limited. A structured and continuous governmental control and regulation of patient safety in relation to the use of eHealth is warranted.

Lung cancer is the most common cancer worldwide and the leading cause of cancer-related deaths in both men and women. Despite the development of novel therapeutic interventions, the 5-year survival rate for non-small cell lung cancer (NSCLC) patients remains low, demonstrating the necessity for novel treatments. One strategy to improve translational research is the development of surrogate models reflecting somatic mutations identified in lung cancer patients as these impact treatment responses. With the advent of CRISPR-mediated genome editing, gene deletion as well as site-directed integration of point mutations enabled us to model human malignancies in more detail than ever before. Here, we report that by using CRISPR/Cas9-mediated targeting of Trp53 and KRas, we recapitulated the classic murine NSCLC model Trp53fl/fl:lsl-KRasG12D/wt. Developing tumors were indistinguishable from Trp53fl/fl:lsl-KRasG12D/wt-derived tumors with regard to morphology, marker expression, and transcriptional profiles. We demonstrate the applicability of CRISPR for tumor modeling in vivo and ameliorating the need to use conventional genetically engineered mouse models. Furthermore, tumor onset was not only achieved in constitutive Cas9 expression but also in wild-type animals via infection of lung epithelial cells with two discrete AAVs encoding different parts of the CRISPR machinery. While conventional mouse models require extensive husbandry to integrate new genetic features allowing for gene targeting, basic molecular methods suffice to inflict the desired genetic alterations in vivo. Utilizing the CRISPR toolbox, in vivo cancer research and modeling is rapidly evolving and enables researchers to swiftly develop new, clinically relevant surrogate models for translational research.

Quantitative assessments of the capacity of marine reserves to restore historical fish body-size distributions require extensive repeated sampling to map the phenotypic responses of target populations to protection. However, the "no take" status of marine reserves oftentimes precludes repeated sampling within their borders and, as a result, our current understanding of the capacity of marine reserves to restore historical body-size distributions remains almost entirely reliant on independent, static visual surveys. To overcome this challenge, we promote the application of a traditional fisheries tool known as a "back-calculation", which allows for the estimation of fish body lengths from otolith annuli distances. This practical application was pursued in this study, using data collected in five marine reserves and adjacent fished reefs in the Philippines, to investigate spatiotemporal disparities in length-at-age of the brown surgeonfish, Acanthurus nigrofuscus. The spatial component of our analyses revealed that 1) A. nigrofuscus were phenotypically similar between marine reserves and fished reefs during their early life history; 2) marine reserve and fished reef populations diverged into significantly different length-at-age morphs between ages three and six, in which protected fish were predominantly larger than conspecifics in fished reefs; and 3) A. nigrofuscus returned to a state of general phenotypic similarity during later life. The temporal component of our analyses revealed that younger generations of A. nigrofuscus exhibited significant, positive year effects that were maintained until age eight, indicating that, within the significant age cohorts, younger generations were significantly larger than older generations.

Objectives: The objectives of this study were to determine the prevalence of attention deficit hyperactivity disorder (ADHD) and specific parental risk factors that may contribute to the development of ADHD in children. Methods: The study was conducted in Oman among fourth-grade students (aged nine to 10 years). A standardized Arabic version of the National Initiative for Children’s Health Quality Vanderbilt Assessment Scale (Teachers questionnaire) was used to determine the presence of ADHD. Parental factors such as socioeconomic status, education, and occupation were documented. Results: The prevalence rate of ADHD was 8.8%. Poor maternal education status, low familial socioeconomic status, and paternal occupation were significantly associated with an increased risk of ADHD. Conclusions: This was the first study that examined familial and parental characteristics of children with ADHD as potential risk factors for the condition. Such psychosocial factors could be employed to further the development of more proficient preventative measures and remedial services.

Introduction: Reference values of oxygen saturation (SpO2) to guide care of low birth weight neonates have been obtained mainly from Caucasians. Data from African newborns are lacking. To determine the pre- and post-ductal SpO2values of low birth weight neonates within the first 72 h of life, compare SpO2values of moderate–late preterm and term low birth weight neonates and determine how mode of delivery affected SpO2in the first 24 h of life. Methodology: An observational descriptive study was carried out on apparently healthy low birth weight newborns weighing 1500 to ≤2499 g. Pre and post ductal SpO2values were recorded at the following hours of life: 10–24 h, >24–48 h and >48–72 h using a NONIN® pulse oximeter. Results: The ranges of pre- and post-ductal SpO2in the study were similar for both preterm and term neonates in the study (89%–100%). The mean (standard deviation [SD]) pre-ductal SpO2was 95.9% (2.3) and the mean (SD) post-ductal SpO2was 95.9% (2.1). There was a significant increase in pre-ductal SpO2from 10 to 24 h through >48–72 h of life (P = 0.027). The mode of delivery did not affect SpO2values within 10–24 h of life. Conclusion: The present study documented daily single pre- and post-ductal SpO2 values for preterm and term low birth weight neonates weighing 1500 g to

Background: Peripheral nerve blocks may provide better conditions for closed reduction of distal radius fractures as compared to other more frequently used modalities. In this systematic review, we evaluate existing evidence on the effect and harm of peripheral nerve blocks for closed reduction of distal radius fractures in adults. Methods: We performed a systematic review with meta‐analysis and trial sequential analysis including trials investigating the use of peripheral nerve blocks for closed reduction of distal radius fractures. Co‐primary outcomes were (1) the quality of the closed reduction measured as the proportion of participants needing surgery afterwards and (2) pain during closed reduction. Results: Six trials (n = 312) met the inclusion criteria. One trial reported on the need for surgery with 4 of 25 participants receiving nerve block compared to 7 of 25 receiving haematoma block needing surgery (RR 0.57, 96.7% CI [0.19; 1.71], p =.50). Four trials reported pain during closed reduction. In a meta‐analysis, pain was not statistically significantly reduced with a nerve block (−2.1 Numeric Rating Scale (NRS) points (0–10), 96.7% CI [−4.4; 0.2], p =.07, tau2 = 5.4, I2 = 97%, TSA‐adj. 95% CI [−11.5; 7.3]). No trial sequential boundaries were crossed, and the required information size was not met. Pre‐planned subgroup analysis on trials evaluating ultrasound guided peripheral nerve blocks (patients = 110) showed a significant decrease in 'pain during reduction' (−4.1 NRS, 96.7% CI [−5.5; −2.6], p <.01, tau2 = 0.9, I2 = 80%). All trial results were at high risk of bias and the certainty of the evidence was very low. Conclusion: The certainty of evidence on the effect of peripheral nerve blocks for closed reduction of distal radius fractures is currently very low. Peripheral nerve blocks performed with ultrasound guidance may potentially reduce pain during closed reduction. High‐quality clinical trials are warranted. [ABSTRACT FROM AUTHOR]

Introduction: This protocol describes a systematic review and meta‐analysis to evaluate the clinical effects of mixing short‐ and long‐acting local anaesthetics in peripheral nerve blocks. Clinicians often combine short‐ and long‐acting local anaesthetics to achieve a briefer onset time. However, this may come with a prize, namely a shorter total duration of the block, which is of clinical importance. Objective: This systematic review aims to strengthen the knowledge of the clinical effects associated with this practice. The primary outcome is the duration of block analgesia. Secondary outcomes are block onset time, sensory and motor block duration. Exploratory outcomes are postoperative pain scores, cumulative 24‐h opioid consumption and the prevalence of serious adverse events. Methods: We will conduct a meta‐analysis of the extracted data, and the risk of bias for each study will be evaluated. We will perform a Trial Sequential Analysis, subgroup, and sensitivity analyses and assess the overall risk of publication bias. Finally, we will evaluate the review using the GRADE principles. [ABSTRACT FROM AUTHOR]