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Abstract Background Sudden onset peri- or post-coital cardiovascular disease is well documented in the literature including myocardial infarction, pulmonary embolus and subarachnoid haemorrhage. The occurrence of aortic dissection in this setting has been reported only once previously. Case presentation We report the case of a 47 year old man who developed sudden onset right leg pain during coitus. This was initially believed to be neurological due to nerve impingement but an MRI failed to identify a prolapse. On further review after 6 weeks, pulses were noted to be absent in the patient's right leg and an urgent vascular review with investigation identified a dissection of the aorta which was subsequently successfully treated. Conclusion This case illustrates a rare presentation of aortic dissection and demonstrates the importance of a thorough vascular assessment in the presence of sudden onset limb pain.

Abstract Introduction Internal jugular vein thrombosis (IJVT) is a rare but potentially fatal condition. It usually arises following trauma to the internal jugular vein but is also seen in association with coagulopathies and advanced malignancies as part of a para-neoplastic syndrome. Case presentation We report a case of a 44 year old woman with a strong past medical history and family history of thrombotic disease who presented with abdominal pain and ascites. A stage III ovarian carcinoma was diagnosed and she underwent debulking of the tumour. She sustained a peri-operative haemorrhage and required insertion of a central line into the right internal jugular vein. At one month follow-up she presented as an emergency with a left neck mass and painful swallowing. A duplex ultrasound of her neck identified a left IJVT to the level of the brachiocephalic vein which had occurred despite warfarinisation and an INR of greater than 2. She was commenced on intravenous heparin and the swelling resolved over the course of a week. Conclusion This case illustrates an unusual presentation of a rare condition. In this case, the precise aetiology is unclear as the IJVT may have been related to a coagulopathy or the presence of advanced malignancy and occurred despite adequate anticoagulation.

Abstract Background As a result of improvements in diagnostic accuracy, the primary source of the tumour is identified in more than 99% of cases presenting with a malignancy. Whilst the axial skeleton is a common site of metastases, the sternum is rarely affected, especially by isolated metastases. Case presentation We report a case of a 68 year old male who was referred to the surgical outpatient clinic with a six month history of sternal pain. The patient was known to have essential thrombocythaemia, which had recently transformed into acute myeloid leukaemia but a sternal biospy showed mucinous adenocarcinoma. He had not localising symptoms and full evaluation failed to localise the primary tumour. Conclusion Solitary sternal metastases are rare and when found an underlying neoplasm is usually identified allowing targeted treatment. If however, there is no symptomatic tumour, the metastasis should simply be treated symptomatically.

Abstract Background The presence of perigraft air is a common finding in the immediate post-operative phase following abdominal aortic aneurysm repair whilst the later appearance of air, in association with elevated inflammatory markers, is regarded as being indicative of the serious complication of graft infection. What is not known is at what timepoint following surgery does the perigraft air become a significant finding. Case Presentation We report the case of a 71 year old man who underwent a computed tomography scan 15 days following repair of an abdominal aortic aneurysm because of the presence of unexplained pyrexia. The scan showed the presence of perigraft air and a small haematoma. The patient was managed conservatively and after 6 weeks the air and haematoma had resolved completely. Conclusion The presence of perigraft air in the early postoperative phase is probably a normal finding, is not associated with graft infection and can be managed non-operatively.

Apolipoprotein B messenger RNA (mRNA) editing enzyme, catalytic polypeptide-like (APOBEC) cytidine deaminases cause genetic instability during cancer development. Elevated APOBEC3A (A3A) levels result in APOBEC signature mutations; however, mechanisms regulating A3A abundance in breast cancer are unknown. Here, we show that dysregulating the ubiquitin-proteasome system with proteasome inhibitors, including Food and Drug Administration-approved anticancer drugs, increased A3A abundance in breast cancer and multiple myeloma cell lines. Unexpectedly, elevated A3A occurs via an ∼100-fold increase in A3A mRNA levels, indicating that proteasome inhibition triggers a transcriptional response as opposed to or in addition to blocking A3A degradation. This transcriptional regulation is mediated in part through FBXO22, a protein that functions in SKP1-cullin-F-box ubiquitin ligase complexes and becomes dysregulated during carcinogenesis. Proteasome inhibitors increased cellular cytidine deaminase activity, decreased cellular proliferation and increased genomic DNA damage in an A3A-dependent manner. Our findings suggest that proteasome dysfunction, either acquired during cancer development or induced therapeutically, could increase A3A-induced genetic heterogeneity and thereby influence therapeutic responses in patients., (© The Author(s) 2023. Published by Oxford University Press on behalf of NAR Cancer.)

The purpose of this pilot study was to investigate the extent to which adults with intellectual disability (ID) met the 2020 Canadian 24-Hour Movement Guidelines. Fifteen adults (six females and nine males) participated in this nine-day observational study (age = 20-64 years) in 2021-2022, during the COVID-19 pandemic. Moderate-to-vigorous physical activity (MVPA), sedentary time, and total sleep time were measured with a smartwatch to compare to the guidelines. A diary subjectively tracked physical activity. Of the 15 participants, 11 met the MVPA guidelines (73%), 4 met the sedentary behaviour guidelines (27%), 7 met the sleep guidelines (47%), and only 1 participant met all 3 of the guidelines (7%). There were no differences in physical activity or sleep between weekends and weekdays, or between males and females. Walking, cleaning dishes, and swimming were the most common types of physical activity performed by the participants. The findings of this pilot study indicate the need to improve sleep and reduce sedentary time in adults with ID. As most participants met the MVPA guidelines, few met the sedentary behaviour guidelines, and nearly half met the sleep guidelines, these data also demonstrate how important it is to assess all three aspects of the movement guidelines. All these behaviours have independent health benefits and risks, which interact to influence overall health.

The initiation, progression, and relapse of cancers often result from mutations occurring within somatic cells. Consequently, processes that elevate mutation rates accelerate carcinogenesis and hinder the development of long-lasting therapeutics. Recent sequencing of human cancer genomes has identified patterns of mutations, termed mutation signatures, many of which correspond to specific environmentally induced and endogenous mutation processes. Some of the most frequently observed mutation signatures are caused by dysregulated activity of APOBECs, which deaminate cytidines in single-stranded DNA at specific sequence motifs causing C-to-T and C-to-G substitutions. In humans, APOBEC-generated genetic heterogeneity in tumor cells contributes to carcinogenesis, metastasis, and resistance to therapeutics. Here, we review the current understanding of APOBECs' role in cancer mutagenesis and impact on disease and the biological processes that influence APOBEC mutagenic capacity.

The cytidine deaminase, APOBEC3A (A3A), is a prominent source of mutations in multiple cancer types. These APOBEC-signature mutations are non-uniformly distributed across cancer genomes, associating with single-stranded (ss) DNA formed during DNA replication and hairpin-forming sequences. The biochemical and cellular factors that influence these specificities are unclear. We measured A3A's cytidine deaminase activity in vitro on substrates that model potential sources of ssDNA in the cell and found that A3A is more active on hairpins containing 4 nt ssDNA loops compared to hairpins with larger loops, bubble structures, replication fork mimics, ssDNA gaps, or linear DNA. Despite pre-bent ssDNAs being expected to fit better in the A3A active site, we determined A3A favors a 4 nt hairpin substrate only 2- to fivefold over linear ssDNA substrates. Addition of whole cell lysates or purified RPA to cytidine deaminase assays more severely reduced A3A activity on linear ssDNA (45 nt) compared to hairpin substrates. These results indicate that the large enrichment of A3A-driven mutations in hairpin-forming sequences in tumor genomes is likely driven in part by other proteins that preferentially bind longer ssDNA regions, which limit A3A's access. Furthermore, A3A activity is reduced at ssDNA associated with a stalled T7 RNA polymerase, suggesting that potential protein occlusion by RNA polymerase also limits A3A activity. These results help explain the small transcriptional strand bias for APOBEC mutation signatures in cancer genomes and the general targeting of hairpin-forming sequences in the lagging strand template during DNA replication., (© 2021. The Author(s).)

The impenetrability of the blood-brain barrier (BBB) to most conventional drugs impedes the treatment of central nervous system (CNS) disorders. Interventions for diseases like brain cancer, neurodegeneration, or age-associated inflammatory processes require varied approaches to CNS drug delivery. Cystine-dense peptides (CDPs) have drawn recent interest as drugs or drug-delivery vehicles. Found throughout the phylogenetic tree, often in drug-like roles, their size, stability, and protein interaction capabilities make CDPs an attractive mid-size biologic scaffold to complement conventional antibody-based drugs. Here, we describe the identification, maturation, characterization, and utilization of a CDP that binds to the transferrin receptor (TfR), a native receptor and BBB transporter for the iron chaperone transferrin. We developed variants with varying binding affinities (K D as low as 216 pM), co-crystallized it with the receptor, and confirmed murine cross-reactivity. It accumulates in the mouse CNS at ~25% of blood levels (CNS blood content is only ~1%-6%) and delivers neurotensin, an otherwise non-BBB-penetrant neuropeptide, at levels capable of modulating CREB signaling in the mouse brain. Our work highlights the utility of CDPs as a diverse, easy-to-screen scaffold family worthy of inclusion in modern drug discovery strategies, demonstrated by the discovery of a candidate CNS drug delivery vehicle ready for further optimization and preclinical development., Competing Interests: Competing Interests Z.R.C., E.J.G., C.Y., G.H., A.D.S., A.J.M., R.K.S., and J.M.O. are listed as authors on patent filings related to technology described in this work. Z.R.C. and G.P.S. have a paid consulting relationship with Blaze Bioscience, Inc. J.M.O. is a founder and shareholder of Blaze Bioscience, Inc. The remaining authors declare no competing financial interests., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

BET-bromodomain inhibition (BETi) has shown pre-clinical promise for MYC-amplified medulloblastoma. However, the mechanisms for its action, and ultimately for resistance, have not been fully defined. Here, using a combination of expression profiling, genome-scale CRISPR/Cas9-mediated loss of function and ORF/cDNA driven rescue screens, and cell-based models of spontaneous resistance, we identify bHLH/homeobox transcription factors and cell-cycle regulators as key genes mediating BETi's response and resistance. Cells that acquire drug tolerance exhibit a more neuronally differentiated cell-state and expression of lineage-specific bHLH/homeobox transcription factors. However, they do not terminally differentiate, maintain expression of CCND2, and continue to cycle through S-phase. Moreover, CDK4/CDK6 inhibition delays acquisition of resistance. Therefore, our data provide insights about the mechanisms underlying BETi effects and the appearance of resistance and support the therapeutic use of combined cell-cycle inhibitors with BETi in MYC-amplified medulloblastoma.

Virtual reality (VR) technology may serve as an effective non-pharmacological analgesic to aid pain management. During VR distraction, the individual is immersed in a game presented through a head-mounted display (HMD). The technological level of the HMD can vary, as can the use of different input devices and the inclusion of sound. While more technologically advanced designs may lead to more effective pain management the specific roles of individual components within such systems are not yet fully understood. Here, the role of supplementary auditory information was explored owing to its particular ecological relevance. Healthy adult participants took part in a series of cold-pressor trials submerging their hand in cold water for as long as possible. Individual pain tolerances were measured according to the time (in seconds) before the participant withdrew their hand. The concurrent use of a VR game and the inclusion of sound was varied systematically within participants. In keeping with previous literature, the use of a VR game increased pain tolerance across conditions. Highest pain tolerance was recorded when participants were simultaneously exposed to both the VR game and supplementary sound. The simultaneous inclusion of sound may therefore play an important role when designing VR to manage pain.

True aneurysms of the axillary artery are rare, most pulsatile masses in the region being pseudoaneurysms. The present study reports a case of a true atherosclerotic axillary artery aneurysm arising in a 65 year old lady which presented with a short history of a painless pulsatile mass and sensory defecit in the hand in the absence of limb trauma. Following preoperative imaging to determine the anatomic details, she underwent repair of the aneurysm and made an excellent symptomatic recovery.

Background: As a result of improvements in diagnostic accuracy, the primary source of the tumour is identified in more than 99% of cases presenting with a malignancy. Whilst the axial skeleton is a common site of metastases, the sternum is rarely affected, especially by isolated metastases., Case Presentation: We report a case of a 68 year old male who was referred to the surgical outpatient clinic with a six month history of sternal pain. The patient was known to have essential thrombocythaemia, which had recently transformed into acute myeloid leukaemia but a sternal biospy showed mucinous adenocarcinoma. He had not localising symptoms and full evaluation failed to localise the primary tumour., Conclusion: Solitary sternal metastases are rare and when found an underlying neoplasm is usually identified allowing targeted treatment. If however, there is no symptomatic tumour, the metastasis should simply be treated symptomatically.