Cdt1 overexpression drives colorectal carcinogenesis through origin overlicensing and DNA damage

Chromatin licensing and DNA replication factor 1 (CDT1), a protein of the pre-replicative complex, is essential for loading the minichromosome maintenance complex (MCM) helicases onto the origins of DNA replication. While several studies have shown that dysregulation of CDT1 expression causes re-replication and DNA damage in cell lines, and CDT1 is highly expressed in several human cancers, whether CDT1 deregulation is sufficient to enhance tumorigenesis in vivo is currently unclear. To delineate its role in vivo, we overexpressed Cdt1 in the mouse colon and induced carcinogenesis using azoxymethane/dextran sodium sulfate (AOM/DSS). Here, we show that mice overexpressing Cdt1 develop a significantly higher number of tumors with increased tumor size, and more severe dysplastic changes (high-grade dysplasia), compared with control mice under the same treatment. These tumors exhibited an increased growth rate, while cells overexpressing Cdt1 loaded greater amounts of Mcm2 onto chromatin, demonstrating origin overlicensing. Adenomas overexpressing Cdt1 showed activation of the DNA damage response (DDR), apoptosis, formation of micronuclei, and chromosome segregation errors, indicating that aberrant expression of Cdt1 results in increased genomic and chromosomal instability in vivo, favoring cancer development. In line with these results, high-level expression of CDT1 in human colorectal cancer tissue specimens and colorectal cancer cell lines correlated significantly with increased origin licensing, activation of the DDR, and microsatellite instability (MSI). © 2022 The Pathological Society of Great Britain and Ireland.     

Feasibility and safety of percutaneous computed tomography guided radiofrequency ablation of lymph nodes in oligometastatic patients: a single center’s experience

Objectives:To retrospectively evaluate feasibility and safety of CT-guided percutaneous radiofrequency ablation (RFA) of metastatic lymph nodes (LN) in terms of achieving local tumor control.Methods:Institutional database research identified 16 patients with 24 metastatic LNs who underwent percutaneous CT-guided radiofrequency ablation. Mean patient age was 66.6 ± 15.70 years (range 40–87) and male/female ratio was 8/8. Contrast-enhanced CT or MRI was used for post-ablation follow-up. Patient and tumor characteristics and RFA technique were evaluated. Technical and clinical success on per tumor and per patient basis as well as complication rates were recorded.Results:Mean size of the treated nodes was 1.78 ± 0.83 cm. The mean number of tumors per patient was 1.5 ± 0.63. The mean procedure time was 56.29 ± 24.27 min including local anesthesia, electrode(s) placement, ablation and post-procedural CT evaluation. Median length of hospital stay was 1.13 ± 0.34 days. On a per lesion basis, the overall complete response post-ablation according to the mRECIST criteria applied was 75% (18/24) of evaluable tumors. Repeat treatment of an index tumor was performed on two patients (three lesions) with complete response achieved in 87.5% (21/24) of evaluable tumors following a second RFA. On a per patient basis, disease progression was noted in 10/16 patients at a mean of 13.9 ± 6.03 months post the ablation procedure.Conclusion:CT-guided percutaneous RFA for oligometastatic LNs is a safe and feasible therapy.Advances in knowledge:With this percutaneous therapeutic option, metastatic LNs can be eradicated with a very low complication rate.     

Flumazenil reduces the duration of thiopentone but not of propofol anaesthesia in humans

The effect of flumazenil (F) on the duration of anaesthesia produced by a single dose of thiopentone (T) and propofol (P) was investigated in a placebo-controlled double-blind trial. Eighty-four patients anaesthetized with N₂O in O₂ and either thiopentone 7 mg · kg^?1 or propofol 3 mg · kg^?1 for minor gynaecological procedures were studied. Patients were randomly allocated to pretreatment with either 0.5 mg of flumazenil (F) or 5 ml of normal saline (NS) in one of the following groups: T/NS, T/F, P/NS, or P/F. Anaesthetic requirements were assessed by recording the time between the injection of anaesthetic and the first movement observed during the procedure. The time elapsed from the administration of thiopentone to the first movement was 6.5 ± 1.6 min for the T/NS group and 5.3 ± 2.4 min for the T/F group (P < 0.05). The first movement after propofol administration was observed at 7.0 ± 2.2 min in the P/NS group and at 7.1 ± 4.5 min in the P/F group (NS). These data suggest that pretreatment with 0.5 mg of flumazenil iv reduces the duration of thiopentone but not of propofol anaesthesia.     

A legal perspective on trust,control and privacy in the context of sexting among children in Europe

ABSTRACT

Children are engaging with technology to establish and maintain intimate relationships and explore their sexual identity. Sexting is one of the ways in which this exploration occurs, often on a consensual basis. In a first stage, this article reflects on the concepts of trust, control and privacy as prerequisites to engage in sexting. In a second stage, the authors explore the extent to which legislative instruments enable the legitimate exploration and expression of one’s sexual identity, and aim to minimise adverse consequences thereof. To that end, the fundamental right to privacy, data protection frameworks and criminal legislation on the non-consensual dissemination of sexual images were identified as potentially harnessing the concepts of trust, control and privacy. Questions were examined regarding the potential undermining thereof through the application of child sexual abuse material legislation to instances of (consensual) sexting between children.     

Multimodal analgesia with gabapentin and local anesthetics prevents acute and chronic pain after breast surgery for cancer

We evaluated the effect of multimodal analgesia on acute and chronic pain after breast surgery for cancer. Fifty patients scheduled for breast cancer surgery were blindly randomized to receive gabapentin, eutectic mixture of local anesthetics cream, and ropivacaine in the wound or three placebos. Pain (visual analog scale) and analgesics were recorded in the postanesthesia care unit (PACU) 3, 6, and 9 h and 8 days after surgery. Three and 6 mo later, patients were assessed for chronic pain. The treatment group consumed less paracetamol in the PACU (469 versus 991 mg; P < 0.002) and less Lonalgal (1.0 versus 4.4 tablets; P = 0.003) than the controls, exhibited lower visual analog scale scores at rest in the PACU (P = 0.001) and on postoperative Days 1, 3, and 5 (P = 0.040, P = 0.015, and P = 0.045, respectively), and after movement in the PACU (P = 0.001) and on postoperative Days 2, 4, and 8 (P = 0.028, P = 0.007, and P = 0.032, respectively). Three and 6 mo after surgery, 18 of 22 (82%) and 12 of 21 (57%) of the controls reported chronic pain versus 10 of 22 (45%) and 6 of 20 (30%) in the treatment group (P = 0.028 and P = 0.424, respectively); 5 of 22 and 4 of 21 of the controls required analgesics versus 0 of 22 and 0 of 20 of those treated (P = 0.048 and P = 0.107, respectively). Multimodal analgesia reduced acute and chronic pain after breast surgery for cancer.     

Systemic ondansetron antagonizes the sensory block produced by intrathecal lidocaine

In this prospective randomized, double-blind study, we investigated the effect of ondansetron on the lidocaine subarachnoid block. Fifty-four male patients scheduled for transurethral surgery under subarachnoid anesthesia received oral ondansetron 4 mg the evening before surgery and 4 mg IV 15 min before subarachnoid anesthesia (ondansetron group) or placebo (placebo group). Two milliliters of 5% hyperbaric lidocaine was administered intrathecally. Sensory block was assessed 20, 25, and 30 min and motor block 30, 60, and 90 min after lidocaine injection. In two patients in the control group and five in the ondansetron group, sensory block was not assessed for technical reasons. In the ondansetron group, sensory block values differed significantly over the 30-min period of assessments (P = 0.048). Fifteen, 20, 25, and 30 min after subarachnoid lidocaine, the level of sensory block was at T11, T12, T12, and T12 in the control group and T12, T12, T12, and L1 in the ondansetron group and differed between groups at 30 min (P = 0.019). Motor block did not differ between the two groups at any study time. We conclude that, under the conditions of our study, ondansetron antagonizes the sensory block produced by lidocaine.     

Anesthesia with 1.5 minimum alveolar concentration sevoflurane is not altered by physostigmine as measured by bispectral and clinical indices

STUDY OBJECTIVE: To evaluate the effect of physostigmine on 1.5% sevoflurane anesthesia and recovery. DESIGN: Prospective, randomized, double-blinded study. SETTING: Operating room of a university-affiliated, metropolitan hospital (Aretaieion Hospital and St Savas Hospital). PATIENTS: Forty female American Society of Anesthesiologists physical status I and II patients scheduled for breast biopsy. INTERVENTIONS: Patients were randomly assigned in physostigmine (PHYSO) and normal-saline (NS) group. Anesthesia was induced with sevoflurane 8% using a vital capacity breath technique, and rocuronium 0.6 mg/kg was given to facilitate Laryngeal Mask Airway (LMA) No. 4 insertion. Anesthesia was maintained with end-tidal sevoflurane 1.5 minimum alveolar concentration (MAC; 3% end-tidal concentration) throughout the procedure. MEASUREMENTS: After skin closure and under steady-state sevoflurane anesthesia 1.5 MAC, heart rate, blood pressure, and Bispectral Index (BIS) were recorded. Immediately after, the PHYSO group received intravenous 2 mg of physostigmine, whereas the NS group received equal volume of normal saline. Bispectral Index and hemodynamic measurements were recorded 5, 8, and 10 minutes after treatment. Anesthesia was then discontinued and the LMA was removed. Zero, 15, and 30 minutes after LMA removal, patients were evaluated for orientation, sedation, sitting ability, and the "picking up matches" test, as well as for nausea and vomiting. MAIN RESULTS: No difference was found in BIS (29 +/- 4, 32 +/- 6, 31 +/- 6, 30 +/- 7, 84 +/- 11 in the PHYSO group vs 29 +/- 6, 30 +/- 6, 30 +/- 5, 31 +/- 5, 86 +/- 7 in the NS group), hemodynamic parameters, or recovery parameters between the 2 groups at any time. No nausea or vomiting was observed in either group. CONCLUSIONS: Physostigmine did not influence BIS values or early recovery when administered to patients anesthetized with 1.5 MAC sevoflurane anesthesia.     

Immediate post-operative effects of tracheotomy on respiratory function during mechanical ventilation

Introduction  

Tracheotomy is widely performed in the intensive care unit after long-term oral intubation. The present study investigates the immediate influence of tracheotomy on respiratory mechanics and blood gases during mechanical ventilation.