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Tumor suppressor and upstream master kinase Liver kinase B1 (LKB1) plays a significant role in suppressing cancer growth and metastatic progression. We show that low-LKB1 expression significantly correlates with poor survival outcome in breast cancer. In line with this observation, loss-of-LKB1 rendered breast cancer cells highly migratory and invasive, attaining cancer stem cell-like phenotype. Accordingly, LKB1-null breast cancer cells exhibited an increased ability to form mammospheres and elevated expression of pluripotency-factors (Oct4, Nanog and Sox2), properties also observed in spontaneous tumors in Lkb1-/- mice. Conversely, LKB1-overexpression in LKB1-null cells abrogated invasion, migration and mammosphere-formation. Honokiol (HNK), a bioactive molecule from Magnolia grandiflora increased LKB1 expression, inhibited individual cell-motility and abrogated the stem-like phenotype of breast cancer cells by reducing the formation of mammosphere, expression of pluripotency-factors and aldehyde dehydrogenase activity. LKB1, and its substrate, AMP-dependent protein kinase (AMPK) are important for HNK-mediated inhibition of pluripotency factors since LKB1-silencing and AMPK-inhibition abrogated, while LKB1-overexpression and AMPK-activation potentiated HNKs effects. Mechanistic studies showed that HNK inhibited Stat3-phosphorylation/activation in an LKB1-dependent manner, preventing its recruitment to canonical binding-sites in the promoters of Nanog, Oct4 and Sox2. Thus, inhibition of the coactivation-function of Stat3 resulted in suppression of expression of pluripotency factors. Further, we showed that HNK inhibited breast tumorigenesis in mice in an LKB1-dependent manner. Molecular analyses of HNK-treated xenografts corroborated our in vitro mechanistic findings. Collectively, these results present the first in vitro and in vivo evidence to support crosstalk between LKB1, Stat3 and pluripotency factors in breast cancer and effective anticancer modulation of this axis with HNK treatment.

In the compulsive gambler process there is a finite set of agents who meet pairwise at random times (i and j meet at times of a rate-vij Poisson process) and, upon meeting, play an instantaneous fair game in which one wins the other’s money. We introduce this process and describe some of its basic properties. Some properties are rather obvious (martingale structure; comparison with Kingman coalescent) while others are more subtle (an “exchangeable over the money elements" property, and a construction reminiscent of the Donnelly-Kurtz look-down construction). Several directions for possible future research are described. One – where agents meet neighbors in a sparse graph – is studied here, and another – a continuous-space extension called the metric coalescent – is studied in Lanoue (2014).

To interpret interacting particle system style models as social dynamics, suppose each pair {i, j} of individuals in a finite population meet at random times of arbitrary specified rates vij, and update theirstates according to some specified rule. The averaging process has real-valued states and the rule: upon meeting, the values Xi(t-),Xj (t-) arereplaced by 1/2 (Xi(t-) + Xj (t-)), 1/2 (Xi(t-) + Xj (t-)). It is curious this simple process has not been studied very systematically. We provide an expository account of basic facts and open problems.

Competing Interests: Declarations. Conflict of interest: The authors declare they have no conflicts of interest.

Background: Ibuprofen is a main cause of drug hypersensitivity reactions in children. The gold standard for diagnosis is the drug provocation test (DPT)., Objective: We aimed to create a clinical risk-stratification tool to guide this high-risk procedure., Methods: We prospectively recruited children with suspected ibuprofen hypersensitivity between January 2017 and March 2024. Using stepwise bidirectional multivariable logistic regression, we calculated a predictive score for a positive ibuprofen DPT., Results: Eighty-two patients with a median age of 5.9 years (interquartile range: 3.4-11.1 years) had an ibuprofen DPT. Eighteen (22.0%) patients had a positive challenge, with an anaphylactic reaction for 11 (61.1%). The I3A score (acronym for ibuprofen, 3As: angioedema, anaphylaxis, age, cutoff of 3) encompasses the following items: angioedema (2 points), anaphylaxis (1 point), and age at reaction ≥10 years old (1 point). The area under the curve of the I3A score was 0.84, and the optimal cutoff of <3 conferred a sensitivity of 84.4% (95% confidence interval [CI]: 66.7%-100.0%) and a specificity of 83.3% (95% CI: 75.0%-92.2%). The negative predictive value was estimated at 94.7% (95% CI: 90.0%-100.0%), and the positive predictive value at 60.0% (95% CI: 46.2%-76.2%). The relative risk of reacting to a challenge in the group I3A 3-4 compared with 0-2 was 11.4 (95% CI: 3.62%-35.7%, P < .001). Anaphylaxis after DPT was observed in 9 of 25 (36.0% [95% CI: 16.0%-56.0%]) in the high-risk group as compared with 2 of 57 (3.5% [95% CI: 0.0%-8.8%]) in the low-risk group (relative risk 10.3 [95% CI: 2.4%-43.5%])., Conclusions: We generated a risk-stratification tool to identify children at low risk of reacting to ibuprofen challenges. Further validation is required in external cohorts., (Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Food allergies, particularly peanut, represent the predominant cause of anaphylaxis. Whereas early allergen introduction has emerged as a potential preventive strategy, the precise impact of recent guidelines on peanut-induced anaphylaxis rates in Canada remains unclear., Objective: To assess the impact of the 2017 Addendum Guidelines for the Prevention of Peanut Allergy on peanut-induced anaphylaxis rates in Canada., Methods: Using a comprehensive longitudinal registry capturing pediatric anaphylaxis presentations to the Montreal's Children's Hospital, we compared children with and without known peanut allergy who presented with peanut-induced anaphylaxis between 2011 and 2019 inclusive, excluding data beyond 2019 owing to the Coronavirus disease 2019 (COVID-19) pandemic. We calculated rates of peanut-induced anaphylaxis presentations per 100,000 age-adjusted all-cause emergency department visits using 4-month intervals. Interrupted time series analysis was used to compare anaphylaxis rate trends before and after 2017 for children ages 0 to 2 and 3 to 17 years., Results: We examined 2,011 cases of pediatric anaphylaxis, including 429 (21%) triggered by peanuts. Compared with pre-guideline estimates, the yearly rate of change of peanut anaphylaxis rates decreased by 7.96 (95% confidence interval -14.57 to -1.36; P = .018) after 2017 among patients with new-onset anaphylaxis in children 2 years of age or younger (n = 109). No significant changes were identified for older patients ages 3 to 17, or in patients with known peanut allergy., Conclusions: Early introduction guidelines in Canada are associated with a reduced risk of new-onset peanut-induced anaphylaxis in young children within a single center in Montreal. Further research is required to assess the impact on a wider population and other food allergens., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Self-reported penicillin allergy labels are common and often inaccurate after assessment. These labels can lead to reduced use of first-line beta-lactam antibiotics and worse outcomes. We measured the impact of a previously performed inpatient proactive systematic penicillin allergy de-labelling program on subsequent antibiotic use. This prior program included assessment, risk-stratification, and low risk direct oral amoxicillin challenge., Methods: We performed a retrospective comparison of parallel cohorts from two separate tertiary care hospital campuses in Ottawa, Canada across two penicillin de-labelling intervention periods across April 15th to April 30th, 2021, and February 15th to March 8th, 2022. Outcomes, including penicillin allergy labelling and antibiotic use, were collected for the index admission and the subsequent 6-month period. Descriptive statistics and multivariate regression analyses were performed., Results: A total of 368 patients with penicillin allergy label were included across two campuses and study periods. 24 (13.8%) patients in the intervention groups had sustained penicillin allergy label removal at 30 days from admission vs. 3 (1.5%) in the non-intervention group (p < 0.001). In the 6-months following admission, beta-lactams were prescribed more frequently in the intervention groups vs. the non-intervention groups for all patients (28 [16.1%] vs.15 [7.7%], p = 0.04) and were prescribed more frequently amongst those who received at least one antibiotic (28/46 [60.9%] vs.15/40 [37.5%], p = 0.097). In a multivariate regression analysis, the intervention groups were found to be associated with an increased odds of beta-lactam prescribing in all patients (OR 2.49, 95%CI 1.29-5.02) and in those prescribed at least one antibiotic (OR 2.44, 95%CI 1.00-6.15). No drug-related adverse events were reported., Conclusions: Proactive penicillin allergy de-labelling for inpatients was associated with a reduction in penicillin allergy labels and increased utilization of beta-lactams in the subsequent 6-months., (© 2024. The Author(s).)

Background: Resource utilization and costs can impede proactive assessment and de-labeling of penicillin allergy among inpatients., Methods: Our pilot intervention was a proactive penicillin allergy de-labeling program for new inpatients with penicillin allergy. Patients deemed appropriate for a challenge with a low-risk penicillin allergy history were administered 250 mg amoxicillin and monitored for 1 h. We performed an explorative economic evaluation using various healthcare professional wages., Results: Over two separate 2-week periods between April 2021 and March 2022, we screened 126 new inpatients with a penicillin allergy. After exclusions, 55 were appropriate for formal assessment. 19 completed the oral challenge, and 12 were directly de-labeled, resulting in a number needed to screen of 4 and a number needed to assess of 1.8 to effectively de-label one patient. The assessor's median time in the hospital per day de-labeling was 4h08 with a range of (0h05, 6h45). A single-site annual implementation would result in 715 penicillin allergy assessments with 403 patients de-labeled assuming 20,234 annual weekday admissions and an 8.9% penicillin allergy rate. Depending on the assessor used, the annual cost of administration would be between $21,476 ($53.29 per effectively de-labeled patient) for a pharmacy technician and $61,121 ($151.67 per effectively de-labeled patient) for a Nurse Practitioner or Physician Assistant., Conclusion: A proactive approach, including a direct oral challenge for low-risk in-patients with penicillin allergy, appears safe and feasible. Similar programs could be implemented at other institutions across Canada to increase access to allergy assessment., (© 2024. The Author(s).)

Background: With ongoing COVID-19 vaccination schedules and the popularity of cosmetic fillers, it is important to examine and record associated adverse reactions to a more general audience of health care professionals. Case reports exist in subspecialty journals outlining reactions after SARS-CoV-2 infection and vaccination. This is one of the first cases published in Canada, and it highlights priorities and challenges faced by physicians in assessing and managing patients presenting with adverse reactions post vaccination., Case Presentation: We present a case of a 43 -year-old women with delayed type 4 hypersensitivity reaction to hyaluronic acid cosmetic filler triggered by COVID-19 mRNA vaccination. We outline the clinical presentation, diagnosis, complications, and treatment of a late inflammatory reaction to hyaluronic acid filler and highlight the treatment priorities for clinicians faced with similar presentations., Conclusion: The differential diagnosis of delayed onset nodules formation post filler injection is broad and includes redistribution of fillers, inflammatory reaction to biofilm, and delayed hypersensitivity reaction. As result, in order to make the right diagnosis, administer the appropriate treatment and achieve great cosmetic results, we highly recommend seeking expert opinion from dermatologist, plastic surgeon and allergist immunologist in a timely manner., (© 2023. The Author(s).)

Background: Many antibiotic allergy labels (AAL) are invalid. Excluding true allergy in people with AAL ("delabeling") could improve health outcomes and decrease costs. Several studies with limited covariate adjustment have associated AAL with a prolonged hospital length of stay (LOS)., Objective: This study determined whether AAL's association with LOS persisted after extensive adjustment for potential confounders and covariates., Methods: All nonpsychiatric admissions to a tertiary care teaching hospital from 2012 to 2015 were included. Generalized estimating equation methods were used to model the daily discharge likelihood as a function of AAL and other important factors (death risk score, daily discharge score, daily severity of illness score, antibiotic use, hospital day and location, weekend-holiday status, and service)., Results: A total of 111,611 admissions (76,460 patients) were studied, in which 16,489 (14.8%) had recorded AAL. Patients with an AAL had a notably greater disease burden: they were older and had more comorbidities, greater health system utilization, and higher death risk. In the univariate analysis, AAL was associated with a significantly decreased daily discharge likelihood (odds ratio [OR], 0.93; [95% confidence interval, 0.90-0.95]). After adjustment for potential confounders and covariates, AAL was not associated with daily discharge likelihood (adjusted OR [aOR] without antibiotics: 1.00 [0.98-1.03]; aOR with antibiotics: 1.02 [0.99-1.04]). Similar results were also seen with penicillin AAL (aOR without antibiotics: 0.99 [0.95-1.02]; aOR with antibiotics: 1.00 [0.96-1.03])., Conclusion: Antibiotic allergy label was strongly associated with a greater disease burden. After adjusting for important covariates, our analysis found no significant association between AAL and hospital LOS., (Copyright © 2022 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Given an edge-weighted tree T with n leaves, sample the leaves uniformly at random without replacement and let W k , 2 ≤ k ≤ n , be the length of the subtree spanned by the first k leaves. We consider the question, "Can T be identified (up to isomorphism) by the joint probability distribution of the random vector ( W 2 , …, W n )?" We show that if T is known a priori to belong to one of various families of edge-weighted trees, then the answer is, "Yes." These families include the edge-weighted trees with edge-weights in general position, the ultrametric edge-weighted trees, and certain families with equal weights on all edges such as ( k + 1)-valent and rooted k -ary trees for k ≥ 2 and caterpillars.

Background: Thrombin activatable fibrinolysis inhibitor (TAFI) is a plasma zymogen, which can be converted to activated TAFI (TAFIa) through proteolytic cleavage by thrombin, plasmin, and most effectively thrombin in complex with the endothelial cofactor thrombomodulin (TM). TAFIa is a carboxypeptidase that cleaves carboxyl terminal lysine and arginine residues from protein and peptide substrates, including plasminogen-binding sites on cell surface receptors. Carboxyl terminal lysine residues play a pivotal role in enhancing cell surface plasminogen activation to plasmin. Plasmin has many critical functions including cleaving components of the extracellular matrix (ECM), which enhances invasion and migration of cancer cells. We therefore hypothesized that TAFIa could act to attenuate metastasis., Methods: To assess the role of TAFIa in breast cancer metastasis, in vitro migration and invasion assays, live cell proteolysis and cell proliferation using MDA-MB-231 and SUM149 cells were carried out in the presence of a TAFIa inhibitor, recombinant TAFI variants, or soluble TM., Results: Inhibition of TAFIa with potato tuber carboxypeptidase inhibitor increased cell invasion, migration and proteolysis of both cell lines, whereas addition of TM resulted in a decrease in all these parameters. A stable variant of TAFIa, TAFIa-CIIYQ, showed enhanced inhibitory effects on cell invasion, migration and proteolysis. Furthermore, pericellular plasminogen activation was significantly decreased on the surface of MDA-MB-231 and SUM149 cells following treatment with various concentrations of TAFIa., Conclusions: Taken together, these results indicate a vital role for TAFIa in regulating pericellular plasminogen activation and ultimately ECM proteolysis in the breast cancer microenvironment. Enhancement of TAFI activation in this microenvironment may be a therapeutic strategy to inhibit invasion and prevent metastasis of breast cancer cells.