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TP53 mutation occurs in 50-75% of human pancreatic ductal adenocarcinomas (PDAC) following an initiating activating mutation in the KRAS gene. These p53 mutations frequently result in expression of a stable protein, p53R¹⁷⁵H, rather than complete loss of protein expression. In this study we elucidate the functions of mutant p53 (Trp53R¹⁷²H), compared to knockout p53 (Trp53fl), in a mouse model of PDAC. First we find that although KrasG¹²D is one of the major oncogenic drivers of PDAC, most KrasG¹²D-expressing pancreatic cells are selectively lost from the tissue, and those that remain form premalignant lesions. Loss, or mutation, of Trp53 allows retention of the KrasG¹²D-expressing cells and drives rapid progression of these premalignant lesions to PDAC. This progression is consistent with failed growth arrest and/or senescence of premalignant lesions, since a mutant of p53, p53R¹⁷²P, which can still induce p21 and cell cycle arrest, is resistant to PDAC formation. Second, we find that despite similar kinetics of primary tumor formation, mutant p53R¹⁷²H, as compared with genetic loss of p53, specifically promotes metastasis. Moreover, only mutant p53R¹⁷²H-expressing tumor cells exhibit invasive activity in an in vitro assay. Importantly, in human PDAC, p53 accumulation significantly correlates with lymph node metastasis. In summary, by using 'knock-in' mutations of Trp53 we have identified two critical acquired functions of a stably expressed mutant form of p53 that drive PDAC; first, an escape from KrasG¹²D-induced senescence/growth arrest and second, the promotion of metastasis.

The success of attempts at opening chronic total occlusions (CTO) has dramatically increased in recent times due to the development of new techniques such as the use of the retrograde approach through epicardial collaterals. However, this approach admittedly brings with it an increased risk, and this must be balanced against the potential benefits. We present the case of a 61-year-old gentleman with Canadian Cardiovascular Society (CCS) Class III angina with a background history of hypertension and dyslipidaemia, who was an ex-smoker, and whose diagnostic coronary angiogram revealed CTOs of both the right and left circumflex coronary arteries. Following a heart team discussion, a percutaneous approach to treatment by staged approach was favoured, with the first stage being opening of the CTO of the right coronary artery. A retrograde approach with the use of a Corsair microcatheter facilitated reverse CART (controlled antegrade and retrograde tracking). Unfortunately, upon removal of the Corsair, a rupture of the epicardial collateral was noted with profuse bleeding into the pericardial space. This was treated successfully with a BeGraft-covered stent to obtain proximal control, and a Cooke Tornado neuro-interventional coil to obtain distal control, delivered antegrade through the now recanalized RCA. This case-based review then highlights several unique learning points, in particular to understand, in general terms, the approach to CTO; to understand the potential complications associated with a retrograde epicardial collateral approach; to understand the stepwise approach to dealing with perforation; and, finally, to understand how an occlusion coil works.

Dysfunction and/or reduced activity in the tongue muscles contributes to conditions such as dysphagia, dysarthria, and sleep disordered breathing. Current treatments are often inadequate, and the tongue is a readily accessible target for therapeutic gene delivery. In this regard, gene therapy specifically targeting the tongue motor system offers two general strategies for treating lingual disorders. First, correcting tongue myofiber and/or hypoglossal (XII) motoneuron pathology in genetic neuromuscular disorders may be readily achieved by intralingual delivery of viral vectors. The retrograde movement of viral vectors such as adeno-associated virus (AAV) enables targeted distribution to XII motoneurons via intralingual viral delivery. Second, conditions with impaired or reduced tongue muscle activation can potentially be treated using viral-driven chemo- or optogenetic approaches to activate or inhibit XII motoneurons and/or tongue myofibers. Further considerations that are highly relevant to lingual gene therapy include (1) the diversity of the motoneurons which control the tongue, (2) the patterns of XII nerve branching, and (3) the complexity of tongue muscle anatomy and biomechanics. Preclinical studies show considerable promise for lingual directed gene therapy in neuromuscular disease, but the potential of such approaches is largely untapped.

Stocking density and trough space allowance can potentially impact sheep welfare during live export voyages. The aim of this study was to assess the welfare implications for sheep housed at five allometric stocking densities, with either unrestricted or restricted trough space allowance. Merino wethers ( n = 720) were housed in 40 pens of 18 heads for 18 days. Two 5-min continuous focal animal observations (n = 3/pen) were conducted on days 3, 5, 11, and 17. Scan sampling of standing and lying behaviours were conducted on the same days at hourly intervals. Live weights and immune cell counts were quantified at the start and end of the experiment, as well as faecal glucocorticoid metabolites (FGCMs), which were also assessed on days 6 and 12. Focal animals housed at higher stocking densities spent less time lying during one of the continuous observation periods, but no important effects on the overall number of animals lying or on the synchronicity of lying were evident. The scan sampling results indicated that the expression of some preferred lying positions was impaired at high stocking densities, and that high stocking densities also resulted in increased agonistic social interactions and displacement events at the start of the trial. There was a slight reduction in day 18 live weights for animals housed at higher stocking densities, but FGCM concentrations and immune cell counts were essentially unaffected. Trough space had no important effects on day 18 live weight, FGCM concentrations, or immune cell counts, and had limited effects on sheep behaviour. The lack of important impacts on biological fitness traits suggests that the behavioural responses observed were sufficient in allowing sheep to cope with their environment. However, we provide evidence that the provision of additional space is beneficial in reducing the time it takes for animals to adapt to their environment and to facilitate the expression of some preferred lying positions. While designed to emulate certain conditions relevant during live export voyages, some factors that may induce stress during this mode of transport were not present such as heat and ocean swell, so the conclusions must be interpreted in the context of the experimental conditions.

Surfing and swimming are two popular outdoor aquatic activities in Australia with an estimated 2.7 million surfers and three million swimmers; however, these activities are associated with intermittent exposure to ultraviolet radiation. Our aim was to determine the point prevalence of pre-skin cancer (actinic keratosis (PSC)), non-melanoma (NMSC) and melanoma skin cancers (MSC) in Australian surfers and swimmers. This cross-sectional study involved Australian surfers who completed a survey that included physiological demographics, aquatic activity-specific demographics, history of skin cancer followed by screening. A total of 171 surfers ( = 116) and swimmers ( = 55) participated in the study. Both groups were identified as having a history of skin cancer (surfers 41.4%, swimmers 36.4%) and a family history of skin cancer (surfers 52.6%, swimmers 43.6%). The majority of both groups reported using a high percentage of a chemical or physical skin cancer prevention strategy (surfers 100%, Swimmers 92.7%, = 0.003). Significantly more surfers were identified with a skin cancer of any type . swimmers (50% . 27.3%; OR 2.67; = 0.005) with most the common skin cancer being PSC (44.7% . 11.3%, = 0.076) followed by basal cell carcinoma (BCC) (24.2% . 7.6%, = 0.068). There was a total of seven MSC identified in surfers and swimmers (4.6% . 0.8%, respectively, = 0.137). Most skin cancers in surfers were located on the face (28.0%) followed by the arm and back (12.1% each), whereas in swimmers, the majority of skin cancers were identified on the face (17.3%), followed by the arm and lower leg (15.4% each). The highest number of melanomas were identified in surfers ( = 6) and mainly located on the face ( = 2) and back ( = 2). There was a single melanoma identified on the back in a swimmer. With the groups combined, the majority (42.9%) of melanomas were identified on the back in participants, followed by the face (28.6%). Rates per 100,000 of NMSC and MSC in surfers and swimmers (respectively) were BCC (11,206 . 14,545), squamous cell carcinoma (SCC) (13,793 . 12,727), SCC (1,724 . 3,636) and MSC (5,172 . 1,818). When compared to the general Australian population, surfers and swimmers had higher odds ratios (OR), which included BCCs (OR 7.3 and 9.4, respectively), SCCs (OR 1.7 and 3.5, respectively) and MSC (OR 96.7 and 18.8, respectively). Surfers and swimmers had consistently higher rates of PSC, NMSC and MSC than the general Australian population. Point prevalence of MSC (groups combined) was 76-fold higher than the general Australian population. These findings highlight the clinical importance of regular skin cancer screenings in individuals who surf or swim for early detection and treatment of skin cancer. Additionally, these aquatic enthusiasts should be advised of the benefits of sun protection strategies such as chemical and physical barriers to reduce the likelihood of developing skin cancer.

[This corrects the article DOI: 10.3389/fvets.2022.965635.].

Pompe disease is caused by mutations in the gene encoding the lysosomal glycogen-metabolizing enzyme, acid-alpha glucosidase (GAA). Tongue myofibers and hypoglossal motoneurons appear to be particularly susceptible in Pompe disease. Here we used intramuscular delivery of adeno-associated virus serotype 9 (AAV9) for targeted delivery of an enhanced form of GAA to tongue myofibers and motoneurons in 6-month-old Pompe (Gaa−/−) mice. We hypothesized that addition of a glycosylation-independent lysosomal targeting tag to the protein would result in enhanced expression in tongue (hypoglossal) motoneurons when compared to the untagged GAA. Mice received an injection into the base of the tongue with AAV9 encoding either the tagged or untagged enzyme; tissues were harvested 4 months later. Both AAV9 constructs effectively drove GAA expression in lingual myofibers and hypoglossal motoneurons. However, mice treated with the AAV9 construct encoding the modified GAA enzyme had a >200% increase in the number of GAA-positive motoneurons as compared to the untagged GAA (p < 0.008). Our results confirm that tongue delivery of AAV9-encoding GAA can effectively target tongue myofibers and associated motoneurons in Pompe mice and indicate that the effectiveness of this approach can be improved by addition of the glycosylation-independent lysosomal targeting tag.

To compare outcomes of percutaneous coronary interventions (PCIs) at 2 community hospitals without on-site surgery (Franciscan Skemp Healthcare and Immanuel St. Joseph's Hospital) with a center with on-site surgery (Saint Marys Hospital). Using a matched case-control design, we studied 1842 elective and 667 nonelective PCI procedures (myocardial infarction [MI]/cardiogenic shock) performed from January 1, 1999, through December 31, 2007. The quality assurance protocol included operator volume and training, application of a risk-adjustment model, transport protocol, and database participation. We compared in-hospital mortality and/or emergent coronary artery bypass surgery after PCI at Franciscan Skemp Healthcare and Immanuel St. Joseph's Hospital, which do not have on-site surgery, with Saint Marys Hospital, a medical center with the capability to perform coronary artery bypass grafting on site. Of 22 baseline variables, significant imbalances between matched groups were present in only 3 (hyperlipidemia, history of MI, American College of Cardiology/American Heart Association B2/C type lesion) in the elective group and 2 (Canadian Cardiovascular Society class III/IV angina, multivessel disease) in the nonelective group. The primary end point occurred in 0.3%, 0.1%, and 0.6% of patients undergoing elective PCI (P=.07) and 3.3%, 3.3%, and 3.7% of patients undergoing nonelective PCI (P=.65) at Immanuel St. Joseph's Hospital, Franciscan Skemp Healthcare, and Saint Marys Hospital, respectively. The in-hospital mortality rate at Immanuel St. Joseph's Hospital and Franciscan Skemp Healthcare was comparable to that at Saint Marys Hospital for both elective (0.3%, 0.1%, 0.4%; P=.24) and nonelective PCI (2.6%, 2.4%, 3.1%; P=.49). No patient undergoing elective PCI required transfer for emergency cardiac surgery. Of the 21 transfers, 20 (95%) were in the setting of MI and cardiogenic shock or left main/3-vessel disease; 18 patients (86%) survived to discharge. Optimal outcomes with PCI have been observed at community hospitals without on-site cardiac surgical programs with application of a prospective, standardized quality assurance protocol.

Abstract Introduction: Alport syndrome is an inherited renal disease characterized by hematuria, renal failure, hearing loss and a lamellated glomerular basement membrane. Patients with Alport syndrome who undergo renal transplantation have been shown to have patient and graft survival rates similar to or better than those of patients with other renal diseases. Methods: In this national case series, based in Beaumont Hospital Dublin, we studied the cohort of patients who underwent renal transplantation over the past 33 years, recorded prospectively in the Irish Renal Transplant Registry, and categorized them according to the presence or absence of Alport syndrome. The main outcomes assessed were patient and renal allograft survival. Results: Fifty-one patients diagnosed with Alport syndrome in Beaumont Hospital received 62 transplants between 1982 and 2014. The comparison group of non-Alport patients comprised 3430 patients for 3865 transplants. Twenty-year Alport patient survival rate was 70.2%, compared to 44.8% for patients with other renal diseases (p = .01). Factors associated with patient survival included younger age at transplantation as well as differences in recipient sex, donor age, cold ischemia time, and episodes of acute rejection. Twenty-year graft survival was 46.8% for patients with Alport syndrome compared to 30.2% for those with non-Alport disease (p = .11). Conclusions: Adjusting for baseline differences between the groups, patients with end-stage kidney disease (ESKD) due to Alport syndrome have similar patient and graft survival to those with other causes of ESKD. This indicates that early diagnosis and management can lead to favorable outcomes for this patient cohort.