What is the role of scientists in meeting the environmental challenges of the twenty-first century?

We live at a time of rapid and accelerating biodiversity loss and climate change that pose an existential risk to the environment, humanity, and social justice and stability. Governmental responses are seen by many citizens, including scientists, as inadequate, leading to an increase in civil protests and activism by those calling for urgent action to effect change. Here we consider the role(s) of scientists in responding to those challenges and engaging with policy given that when a scientist moves into political advocacy, reflecting their values and preferences, their objectivity and the value of scientific opinion may be seen as compromised. We then consider whether institutional setting and career stage may affect decisions to engage with policy or activism. Against this backcloth, we ask whether it is sufficient for scientists to act as impartial 'brokers' in societal decisions, arguing they should consider acting as 'Honest Advocates' in policy formation in some circumstances. Such advocacy can contribute to decision-making in a purposeful, well-informed manner, doing societal good without damaging the reputation of science. We encourage scientists to each reflect on their multiple roles in addressing the environmental challenges of our time.

The Management of Dysfunctional Gallbladder Disease and the Role of Laparoscopic Cholecystectomy on Symptom Improvement: A Retrospective Cohort Study.

Background Biliary dyskinesia (BD) is a disorder characterised by abdominal pain of biliary origin (i.e., sudden steady pain at the right upper quadrant of the abdomen or the epigastrium, the absence of gallstones on ultrasound (US)), and a decreased gallbladder ejection fraction (GBEF) on a cholecystokinin-cholescintigraphy hepatobiliary iminodiacetic acid (CCK-HIDA) scan. Patients experiencing symptoms suggestive of biliary obstruction, but lacking gallstones, yet exhibiting abnormal gallbladder emptying, may find therapeutic benefit from laparoscopic cholecystectomy. Common symptoms include recurrent, intense, and enduring pain, often exacerbated by fatty food consumption, localised in the upper right quadrant or epigastric region. This pain may radiate to the back or shoulder, persisting for at least 30 minutes but not exceeding several hours, and it is sometimes accompanied by nausea and vomiting. Abnormal gallbladder emptying is typically indicated by a GBEF below 35% on cholescintigraphy following cholecystokinin administration. Objective This study represents a single-centric review focusing on 88 patients over a five-year period who presented with features of dysfunctional gallbladder and underwent cholescintigraphy. The primary aim was to identify whether there is any role for laparoscopic cholecystectomy in symptom improvement among these patients. Methods This was a retrospective cohort study involving data collection using electronic medical records. Eighty-eight patients who underwent the HIDA scan between January 2019 and December 2023 at Wirral University Teaching Hospital NHS Foundation Trust (WUTH) were identified and separated into two groups, either hypofunctioning gallbladder (EF<35% ) or hyperfunctioning gallbladder (EF>80%). Normal HIDA scan patients (EF between 35%-80%) were excluded. The frequency of laparoscopic cholecystectomy and subsequent symptom improvement were recorded. Results Fifty-one patients were diagnosed with gallbladder dyskinesia (BD). Of these, 36 patients (30 females, mean age 43) were diagnosed with hypofunctional gallbladder (EF<35%), where 17 patients underwent laparoscopic cholecystectomy, resulting in symptom improvement in 10 patients (58.8%). Conversely, 15 patients were diagnosed with hyperfunctional gallbladder (13 females, mean age 48.6). Only two patients (13%) underwent laparoscopic cholecystectomy with 100% symptom improvement in both patients. Conclusions In conclusion, our retrospective study highlights the significance of the HIDA scan in identifying gallbladder hypofunction among patients presenting with biliary symptoms. The findings establish the efficacy of laparoscopic cholecystectomy as a management approach, with a notable proportion of patients experiencing symptom improvement (58.8%). These results contribute to our understanding of biliary dysfunction management and emphasise the importance of individualised treatment strategies for optimal patient outcomes. Further, randomised controlled trials (RCTs) are warranted to validate these findings and explore additional factors influencing symptom resolution in this patient population.

The epidemiology of acute pancreatitis in Tasmania over a 12-year period: Is this a disease of disadvantage?

BACKGROUND: The global incidence of acute pancreatitis (AP) is increasing, but little information exists about trends in Australia. This study aimed to describe incidence trends, along with clinical and socio-demographic associations, in the state of Tasmania over a recent 12-year period. METHODS: The study cohort was obtained by linking clinical and administrative datasets encompassing the whole Tasmanian population between 2007 and 2018, inclusive. Pancreatitis case definition was based on relevant ICD-10 hospitalization codes, or elevated serum lipase or amylase in pathology data. Age-standardised incidence rates were estimated, overall and stratified by sex, aetiology, and Index of Relative Socio-economic Disadvantage (IRSD). RESULTS: In the study period, 4905 public hospital AP episodes were identified in 3503 people. The age-standardised person-based incidence rate across the entire period was 54 per 100,000 per year. Incidence was inversely related to IRSD score; 71 per 100,000 per year in the most disadvantaged quartile compared to 32 in the least disadvantaged. Biliary AP incidence was higher than that of alcohol-related AP, although the greatest incidence was in "unspecified" cases. There was an increase in incidence for the whole cohort (average annual percent change 3.23 %), largely driven by the two most disadvantaged IRSD quartiles; the least disadvantaged quartile saw a slight overall decrease. CONCLUSION: This is the first Australian study providing robust evidence that AP incidence is increasing and is at the upper limit of population-based studies worldwide. This increased incidence is greatest in socio-economically disadvantaged areas, meriting further research to develop targeted, holistic management strategies.

The Safety of Incisional Hernia Surgical Repair in Patients ≥70 Years.

Introduction Incisional hernias (IHs) are common complications of abdominal surgery. Frailty and advancing age could be related to poor outcomes after surgical interventions, especially after operating on challenging surgical fields with adhesions and dense scars. This study assesses the safety of IH surgical repair in patients aged 70 years and above. Methods A retrospective analysis of all patients who had IH surgical repair on an emergency and elective basis at a district hospital in the UK. The cohort was categorised into group I (<70 years) and group II (≥70 years). A comparative analysis was conducted between these groups based on demographic data, comorbidities, hernia characteristics, operative data, and patient outcomes. Results This study encompassed 262 patients, with a mean age of 61.8 SD± 14.2 years, of whom 152 (58%) were females. Of these, group I comprised 173, and group II included 89 patients. Notably, group I exhibited a higher prevalence of morbid obesity, with 46 (28.8%) cases, as opposed to 12 (15.2%) in group II; p=0.021. Conversely, group II demonstrated a greater incidence of individuals with at least one comorbidity and chronic obstructive pulmonary disease (COPD) than group I, p=0.004 and 0.003, respectively. Fifty-five (32%) and 49 (29.3%) of group I had multiple defects and recurrent hernias compared to 24 (28.2%) and 16 (18.8%) in group II, p=0.541 and 0.071, respectively. The mean hospital stays were 5.5 ± 8.3 and 8.33 ± 18.7 days, and the mean durations of surgery were 131.6 ± 105.2 and 106.73 ± 74.22 minutes in groups I and II, p=0.057 and 0.181, respectively. No significant differences were observed in overall or wound-related complications, p=0.587 and 0.125. The rates of mortality within 30 days were three (1.7%) in group I and three (3.4%) in group II, with 90-day mortality rates at four (2.3%) and three (3.4%), respectively, indicating no significant difference. Similarly, no significant differences emerged between the groups regarding hernia recurrence rates (with a mean follow-up of 56 months) or 90-day readmission rates. Conclusions Surgical repair of IH is safe and effective in patients ≥70 years with comparable outcomes to younger patients.

Outcomes of Surgical Repair of Incisional Hernia in Patients With Severe and Morbid Obesity: A Comparative Study.

Introduction Incisional hernia (IH) is a common complication after open and minimal access abdominal surgery. The current practice guidelines recommend weight reduction to achieve a body mass index (BMI) < 35 kg/m2 before surgical repair of ventral hernias. However, this could be challenging to achieve, especially in emergency presentations. This study aims to assess the safety of surgical repair of IH in patients with BMI ≥35 kg/m2. Methods A retrospective comparative study has been conducted to include all patients who had surgical repair of IH on an elective and emergency basis in a UK District General Hospital. The patients were divided into two groups. Group I BMI < 35 kg/m2 and Group II with BMI ≥35 kg/m2. A comparison was made between the two groups according to demographics, comorbidities, hernia characteristics, operative data, and outcomes. Results The study included 239 patients, 181 in Group I and 58 in Group II. Morbid obesity was associated with male patients, and they were younger than Group I, p= 0.001 and 0.013, respectively. 13.8% of Group I had DM compared to 29.3% in Group II, p= 0.007. There were no significant differences in hernia characteristics or mode of surgery between the two groups. However, Group II had more overall and wound-related complications, p= <0.001 each. There were no significant differences in 30-day and 90-day mortality, recurrence rate, or 90-day readmissions. Conclusions Surgical repair of IH in patients with severe and morbid obesity is associated with more overall and wound-related complications.

Proteomic profiling of small extracellular vesicles derived from mouse pancreatic cancer and stellate cells: Role in pancreatic cancer.

Small extracellular vesicles (sEVs) are cell-derived vesicles evolving as important elements involved in all stages of cancers. sEVs bear unique protein signatures that may serve as biomarkers. Pancreatic cancer (PC) records a very poor survival rate owing to its late diagnosis and several cancer cell-derived proteins have been reported as candidate biomarkers. However, given the pivotal role played by stellate cells (PSCs, which produce the collagenous stroma in PC), it is essential to also assess PSC-sEV cargo in biomarker discovery. Thus, this study aimed to isolate and characterise sEVs from mouse PC cells and PSCs cultured alone or as co-cultures and performed proteomic profiling and pathway analysis. Proteomics confirmed the enrichment of specific markers in the sEVs compared to their cells of origin as well as the proteins that are known to express in each of the culture types. Most importantly, for the first time it was revealed that PSC-sEVs are enriched in proteins (including G6PI, PGAM1, ENO1, ENO3, and LDHA) that mediate pathways related to development of diabetes, such as glucose metabolism and gluconeogenesis revealing a potential role of PSCs in pancreatic cancer-related diabetes (PCRD). PCRD is now considered a harbinger of PC and further research will enable to identify the role of these components in PCRD and may develop as novel candidate biomarkers of PC.

A patient-centered evaluation of a novel medical student-based patient navigation program.

OBJECTIVES: Understand the patient experience of a pilot medical student-based patient navigator (PN) program. (2) Assess areas of improvement for further development as a model for expansion. METHODS: This was a cross-sectional study assessing patients' subjective experience of medical student navigators for rheumatological conditions. Current student navigators contacted enrolled patients by phone with both structured and free-response questions. RESULTS: 44 of 71 patients completed the questionnaire. 84% reported a satisfaction of ≥ 4 on a 5 point Likert scale. > 80% of patients felt that the program helped them better care for their health, feel more understood by their medical team, and feel cared for by their healthcare team. Medical student navigators were able to assist with most patient requests. CONCLUSIONS: Patients enrolled in our medical student PN program expressed high levels of satisfaction and felt better able to access health resources with the help of a navigator. PRACTICE IMPLICATIONS: Employing medical students as PNs may serve as a mutually beneficial intervention providing early clinical exposure to students while furthering patient access to care. Other institutions may benefit from similarly structured interventions.

A horizon scan of global biological conservation issues for 2024.

We present the results of our 15th horizon scan of novel issues that could influence biological conservation in the future. From an initial list of 96 issues, our international panel of scientists and practitioners identified 15 that we consider important for societies worldwide to track and potentially respond to. Issues are novel within conservation or represent a substantial positive or negative step-change with global or regional extents. For example, new sources of hydrogen fuel and changes in deep-sea currents may have profound impacts on marine and terrestrial ecosystems. Technological advances that may be positive include benchtop DNA printers and the industrialisation of approaches that can create high-protein food from air, potentially reducing the pressure on land for food production.

HGF/c-Met pathway inhibition combined with chemotherapy increases cytotoxic T-cell infiltration and inhibits pancreatic tumour growth and metastasis.

Pancreatic cancer (PC) is a deadly cancer with a high mortality rate. The unique characteristics of PC, including desmoplasia and immunosuppression, have made it difficult to develop effective treatment strategies. Pancreatic stellate cells (PSCs) play a crucial role in the progression of the disease by interacting with cancer cells. One of the key mediators of PSC - cancer cell interactions is the hepatocyte growth factor (HGF)/c-MET pathway. Using an immunocompetent in vivo model of PC as well as in vitro experiments, this study has shown that a combined approach using HGF/c-MET inhibitors to target stromal-tumour interactions and chemotherapy (gemcitabine) to target cancer cells effectively decreases tumour volume, EMT, and stemness, and importantly, eliminates metastasis. Notably, HGF/c-MET inhibition decreases TGF-ß secretion by cancer cells, resulting in an increase in cytotoxic T-cell infiltration, thus contributing to cancer cell death in tumours. HGF/c-MET inhibition + chemotherapy was also found to normalise the gut microbiome and improve gut microbial diversity. These findings provide a strong platform for assessment of this triple therapy (HGF/c-MET inhibition + chemotherapy) approach in the clinical setting.

The Functional Anatomy and Innervation of the Platysma is Segmental: Implications for Lower Lip Dysfunction, Recurrent Platysmal Bands, and Surgical Rejuvenation.

BACKGROUND: Despite the central role of the platysma in face and neck rejuvenation, much confusion exists regarding its surgical anatomy. OBJECTIVES: This study was undertaken to clarify the regional anatomy of the platysma and its innervation pattern and to explain clinical phenomena, such as the origin of platysmal bands and their recurrence, and the etiology of lower lip dysfunction after neck lift procedures. METHODS: Fifty-five cadaver heads were studied (16 embalmed, 39 fresh, mean age 75 years). Following preliminary dissections and macro-sectioning, a series of standardized layered dissections were performed, complemented by histology and sheet plastination. RESULTS: In addition to its origin and insertion, the platysma is attached to the skin and deep fascia across its entire superficial and deep surfaces. This composite system explains the age-related formation of static platysmal bands, recurrent platysmal bands after complete platysma transection, and recurrent anterior neck laxity after no-release lifting. The facial part of the platysma is primarily innervated by the marginal mandibular branch of the facial nerve, whereas the submandibular platysma is innervated by the "first" cervical branches, which terminate at the mandibular origin of the depressor labii inferioris. This pattern has implications for postoperative dysfunction of the lower lip, including pseudoparalysis, and potential targeted surgical denervation. CONCLUSIONS: This anatomical study, comprised of layered dissections, large histology, and sheet plastination, fully describes the anatomy of the platysma including its bony, fascial, and dermal attachments, as well as its segmental innervation including its nerve danger zones. It provides a sound anatomical basis for the further development of surgical techniques to rejuvenate the neck with prevention of recurrent platysmal banding.

Correlation with a limited set of behavioral niches explains the convergence of somatic morphology in mygalomorph spiders.

Understanding the drivers of morphological convergence requires investigation into its relationship with behavior and niche space, and such investigations in turn provide insights into evolutionary dynamics, functional morphology, and life history. Mygalomorph spiders (trapdoor spiders and their kin) have long been associated with high levels of morphological homoplasy, and many convergent features can be intuitively associated with different behavioral niches. Using genus-level phylogenies based on recent genomic studies and a newly assembled matrix of discrete behavioral and somatic morphological characters, we reconstruct the evolution of burrowing behavior in the Mygalomorphae, compare the influence of behavior and evolutionary history on somatic morphology, and test hypotheses of correlated evolution between specific morphological features and behavior. Our results reveal the simplicity of the mygalomorph adaptive landscape, with opportunistic, web-building taxa at one end, and burrowing/nesting taxa with structurally modified burrow entrances (e.g., a trapdoor) at the other. Shifts in behavioral niche, in both directions, are common across the evolutionary history of the Mygalomorphae, and several major clades include taxa inhabiting both behavioral extremes. Somatic morphology is heavily influenced by behavior, with taxa inhabiting the same behavioral niche often more similar morphologically than more closely related but behaviorally divergent taxa, and we were able to identify a suite of 11 somatic features that show significant correlation with particular behaviors. We discuss these findings in light of the function of particular morphological features, niche dynamics within the Mygalomorphae, and constraints on the mygalomorph adaptive landscape relative to other spiders.

A global biological conservation horizon scan of issues for 2023.

We present the results of our 14th horizon scan of issues we expect to influence biological conservation in the future. From an initial set of 102 topics, our global panel of 30 scientists and practitioners identified 15 issues we consider most urgent for societies worldwide to address. Issues are novel within biological conservation or represent a substantial positive or negative step change at global or regional scales. Issues such as submerged artificial light fisheries and accelerating upper ocean currents could have profound negative impacts on marine or coastal ecosystems. We also identified potentially positive technological advances, including energy production and storage, improved fertilisation methods, and expansion of biodegradable materials. If effectively managed, these technologies could realise future benefits for biological diversity.

Incisional Hernia: A Surgical Complication or Medical Disease?

Incisional hernia (IH) is a frequent complication following abdominal surgery. The development of IH could be more sophisticated than a simple anatomical failure of the abdominal wall. Reported IH incidence varies among studies. This review presented an overview of definitions, molecular basis, risk factors, incidence, clinical presentation, surgical techniques, postoperative care, cost, risk prediction tools, and proposed preventative measures. A literature search of PubMed was conducted to include high-quality studies on IH. The incidence of IH depends on the primary surgical pathology, incision site and extent, associated medical comorbidities, and risk factors. The review highlighted inherent and modifiable risk factors. The disorganisation of the extracellular matrix, defective fibroblast functions, and ratio variations of different collagen types are implicated in molecular mechanisms. Elective repair of IH alleviates symptoms, prevents complications, and improves the quality of life (QOL). Recent studies introduced risk prediction tools to implement preventative measures, including suture line reinforcement or prophylactic mesh application in high-risk groups. Elective repair improves QOL and prevents sinister outcomes associated with emergency IH repair. The watchful wait strategy should be reviewed, and options should be discussed thoroughly during patients' counselling. Risk stratification tools for predicting IH would help adopt prophylactic measures.

Mental Health of Emergency Department Healthcare Workers During COVID-19 in Brooklyn, New York.

Background: Maintaining good mental health among Emergency Department healthcare workers (ED HCW) is paramount to well-functioning healthcare. We measured mental health and COVID-19 symptoms in ED HCW at a COVID-19 epicenter. Methods: A cross-sectional, convenience sample of adult (≥18 years) ED HCW in Brooklyn, New York, USA, who were employed at ≥50% of a full-time effort, was surveyed September-December, 2020 with reference period March-May 2020. An anonymous email-distributed survey assessed gender, age, race, healthcare worker status (clinical versus non-clinical), SARS-CoV-2 testing, number of people to talk to, COVID-19-related home problems, mental health care interruption during COVID-19, loneliness, and survey date. Outcomes included symptoms of depression, psychological distress, perceived stress, post-traumatic stress disorder (PTSD), anxiety, and resilience measured using validated scales. Results: Of 774 HCW, 247 (31.9%) responded (mean age 38.2±10.8 years; 59.4% White; 52.5% men; 80.1% clinical; 61.6% SARS-CoV-2 tested). Average mental health scores were significantly higher among clinical vs non-clinical HCW (P's<0.0001-0.019). The proportion reporting a clinically-relevant psychological distress symptom burden was higher among clinical vs non-clinical HCW (35.8% vs 13.8%, p=0.019); and suggested for depression (53.9% clinical vs 35.7% non-clinical, p=0.072); perceived stress (63.6% clinical vs 44.8% non-clinical, p=0.053); and PTSD (18.2% clinical vs 3.6% non-clinical, p=0.064). Compared to non-clinical staff, Medical Doctors and Doctors of Osteopathy reported 4.8-fold higher multivariable-adjusted odds of clinically-relevant perceived stress (95%CI 1.8-12.9, p=0.002); Emergency Medical Technicians reported 15.5-fold higher multivariable-adjusted odds of clinically-relevant PTSD (95%CI 1.6-150.4, p=0.018). Increasing age, number of COVID-19-related home problems and people to talk to, loneliness and mental health care interruption were adversely associated with mental health; being male and SARS-CoV-2 testing were beneficial. Conclusions: COVID-19-related mental health burden was high among ED HCW in Brooklyn. Mental health support services are essential for ED HCW.

The influence of preoperative CT imaging on surgical delay in patients with acutely symptomatic abdominal wall hernias.

PURPOSE: Abdominal wall hernias are common in the UK and many present in an emergent fashion. The widespread introduction of computed tomography (CT) imaging has transformed surgical practice but out of hours access can be limited by hospital resources and introduce delays. We investigated the influence of preoperative CT imaging in acutely symptomatic hernia and the association with surgical delay and risks of bowel ischemia. METHODS: A retrospective analysis of patients undergoing emergency hernia surgery between 2013 and 2021 in a busy UK district general hospital. We evaluated the role of preoperative CT and its influence on timing of surgery, postoperative complications, critical care admission and hospital length of stay. RESULTS: Five hundred and five patients were studied. Of these, 191 had a preoperative CT scan. Sites of hernia included inguinal in 164 patients (33%); umbilical in 164 (33%); femoral in 69 (14%); incisional in 69 (14%); epigastric in 30 (6%) and Spigelian hernia 9 (2%). Preoperative CT imaging was associated with surgical delay (22.0 h vs 13.0 h, p < 0.001) and an increased need for bowel resection (12% vs 6%, p = 0.027). Delay in surgery was not associated with increased postoperative complications (5% vs 4%, p = 0.474) but was associated with increased critical care admission (11.0% vs 4.8%, p = 0.014). CONCLUSIONS: Preoperative CT scan for emergent hernias can delay often inevitable surgery and is associated with an increasing need for more complex, resectional surgery .

Small extracellular vesicles (exosomes) and their cargo in pancreatic cancer: Key roles in the hallmarks of cancer.

Pancreatic cancer (PC) is a devastating disease, offering poor mortality rates for patients. The current challenge being faced is the inability to diagnose patients in a timely manner, where potentially curative resection provides the best chance of survival. Recently, small/nanosized extracellular vesicles (sEVs), including exosomes, have gained significant preclinical and clinical attention due to their emerging roles in cancer progression and diagnosis. Extracellular vesicles (EVs) possess endogenous properties that offer stability and facilitate crossing of biological barriers for delivery of molecular cargo to cells, acting as a form of intercellular communication to regulate function and phenotype of recipient cells. This review provides an overview of the role of EVs, their subtypes and their oncogenic cargo (as characterised by targeted studies as well as agnostic '-omics' analyses) in the pathobiology of pancreatic cancer. The discussion covers the progress of 'omics technology' that has enabled elucidation of the molecular mechanisms that mediate the role of EVs and their cargo in pancreatic cancer progression.

The influence of intraoperative rectal washout on local recurrence of colorectal cancer following curative resection: a systematic review and meta-analysis.

PURPOSE: To determine the effectiveness of rectal washout in preventing local recurrence of distal colorectal cancer following curative resection. METHODS: A systematic review and meta-analysis was performed after a literature search was conducted on MEDLINE, EMBASE, the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP), ClinicalTrials.gov, and the ISRCTN registry. The study was reported using PRISMA guidelines. The primary endpoint was incidence of local recurrence of cancer after distal colonic and rectal cancer surgery. RESULTS: After screening, 8 studies with a total sample size of 6739 patients were identified. At 5-year follow-up, local recurrence in the washout group (WO) was 6.08% compared to 9.48% in the no-washout group (NWO) group (OR 0.63, 95% CI = 0.51-0.78, Chi2 = 6.76, df = 7, p = 0.45). The relative risk reduction was 36.9%. To exclude a 36.9% relative risk reduction from 9.48 to 6.08% with a 5% significance level and 80% power a randomized control trial would require a total sample size of 1946 participants distributed equally between the two treatment arms. CONCLUSION: It is safe to recommend the use of rectal washout for left sided and rectal tumour resections. It is a simple and safe step during colorectal surgery that appears to improve long-term oncological outcomes and was not reported to be associated with any complications.

Metastatic phenotype and immunosuppressive tumour microenvironment in pancreatic ductal adenocarcinoma: Key role of the urokinase plasminogen activator (PLAU).

Background: Previous studies have revealed the role of dysregulated urokinase plasminogen activator (encoded by PLAU) expression and activity in several pathways associated with cancer progression. However, systematic investigation into the association of PLAU expression with factors that modulate PDAC (pancreatic ductal adenocarcinoma) progression is lacking, such as those affecting stromal (pancreatic stellate cell, PSC)-cancer cell interactions, tumour immunity, PDAC subtypes and clinical outcomes from potential PLAU inhibition. Methods: This study used an integrated bioinformatics approach to identify prognostic markers correlated with PLAU expression using different transcriptomics, proteomics, and clinical data sets. We then determined the association of dysregulated PLAU and correlated signatures with oncogenic pathways, metastatic phenotypes, stroma, immunosuppressive tumour microenvironment (TME) and clinical outcome. Finally, using an in vivo orthotopic model of pancreatic cancer, we confirmed the predicted effect of inhibiting PLAU on tumour growth and metastasis. Results: Our analyses revealed that PLAU upregulation is not only associated with numerous other prognostic markers but also associated with the activation of various oncogenic signalling pathways, aggressive phenotypes relevant to PDAC growth and metastasis, such as proliferation, epithelial-mesenchymal transition (EMT), stemness, hypoxia, extracellular cell matrix (ECM) degradation, upregulation of stromal signatures, and immune suppression in the tumour microenvironment (TME). Moreover, the upregulation of PLAU was directly connected with signalling pathways known to mediate PSC-cancer cell interactions. Furthermore, PLAU upregulation was associated with the aggressive basal/squamous phenotype of PDAC and significantly reduced overall survival, indicating that this subset of patients may benefit from therapeutic interventions to inhibit PLAU activity. Our studies with a clinically relevant orthotopic pancreatic model showed that even short-term PLAU inhibition is sufficient to significantly halt tumour growth and, importantly, eliminate visible metastasis. Conclusion: Elevated PLAU correlates with increased aggressive phenotypes, stromal score, and immune suppression in PDAC. PLAU upregulation is also closely associated with the basal subtype type of PDAC; patients with this subtype are at high risk of mortality from the disease and may benefit from therapeutic targeting of PLAU.