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Bronchopulmonary dysplasia (BPD) is the most common complication of prematurity. Oxidative stress (OS) and inflammation are the major contributors to BPD. Despite aggressive treatments, BPD prevalence remains unchanged, which underscores the urgent need to explore more potential therapies. The endoplasmic reticulum (ER) plays crucial roles in surfactant and protein synthesis, assisting mitochondrial function, and maintaining metabolic homeostasis. Under OS, disturbed metabolism and protein folding transform the ER structure to refold proteins and help degrade non-essential proteins to resume cell homeostasis. When OS becomes excessive, the endogenous chaperone will leave the three ER stress sensors to allow subsequent changes, including cell death and senescence, impairing the growth potential of organs. The contributing role of ER stress in BPD is confirmed by reproducing the BPD phenotype in rat pups by ER stress inducers. Although chemical chaperones attenuate BPD, ER stress is still associated with cellular senescence. N-acetyl-lysyltyrosylcysteine amide (KYC) is a myeloperoxidase inhibitor that attenuates ER stress and senescence as a systems pharmacology agent. In this review, we describe the role of ER stress in BPD and discuss the therapeutic potentials of chemical chaperones and KYC, highlighting their promising role in future therapeutic interventions.

Bronchopulmonary dysplasia (BPD) is a lung complication of premature births. The leading causes of BPD are oxidative stress (OS) from oxygen treatment, infection or inflammation, and mechanical ventilation. OS activates alveolar myeloid cells with subsequent myeloperoxidase (MPO)-mediated OS. Premature human neonates lack sufficient antioxidative capacity and are susceptible to OS. Unopposed OS elicits inflammation, endoplasmic reticulum (ER) stress, and cellular senescence, culminating in a BPD phenotype. Poor nutrition, patent ductus arteriosus, and infection further aggravate OS. BPD survivors frequently suffer from reactive airway disease, neurodevelopmental deficits, and inadequate exercise performance and are prone to developing early-onset chronic obstructive pulmonary disease. Rats and mice are commonly used to study BPD, as they are born at the saccular stage, comparable to human neonates at 22–36 weeks of gestation. The alveolar stage in rats and mice starts at the postnatal age of 5 days. Because of their well-established antioxidative capacities, a higher oxygen concentration (hyperoxia, HOX) is required to elicit OS lung damage in rats and mice. Neutrophil infiltration and ER stress occur shortly after HOX, while cellular senescence is seen later. Studies have shown that MPO plays a critical role in the process. A novel tripeptide, N-acetyl-lysyltyrosylcysteine amide (KYC), a reversible MPO inhibitor, attenuates BPD effectively. In contrast, the irreversible MPO inhibitor—AZD4831—failed to provide similar efficacy. Interestingly, KYC cannot offer its effectiveness without the existence of MPO. We review the mechanisms by which this anti-MPO agent attenuates BPD.

Abstract Aims N‐terminal pro‐b‐type natriuretic peptide (NT‐proBNP) values may be influenced by patient factors beyond the severity of illness, including atrial fibrillation (AF), renal dysfunction, or increased body mass index (BMI). We hypothesized that these factors may influence the achievement of NT‐proBNP targets and clinical outcomes. Methods A total of 894 patients with heart failure with reduced ejection fraction were enrolled in The Guiding Evidence‐Based Therapy Using Biomarker Intensified Treatment trial. NT‐proBNP was analysed every 3 months. Results Forty per cent of patients had AF, the median estimated glomerular filtration rate (eGFR) was 59 mL/min/1.73 m2 [interquartile range (IQR) 43–76], and median BMI was 29 kg/m2 (IQR 25–34). Patients with AF, eGFR 60 mL/min/1.73 m2, P

BACKGROUND: Surgical and adjuvant management of mucinous cystic neoplasms (MCNs) lacks formal guidelines and data is limited to institutional studies. Factors associated with receipt of adjuvant therapy and any associated impact on survival remain to be clarified. In the absence of other data, guidelines that recommend adjuvant chemotherapy for invasive pancreatic adenocarcinoma have been extrapolated to MCN. PATIENTS AND METHODS: The National Cancer Database (2004-2019) was utilized to identify all patients that underwent pancreatic resection for invasive MCNs. Patients that received neoadjuvant therapy or did not undergo lymphadenectomy were excluded. Patient, tumor, and treatment factors associated with survival were assessed. RESULTS: For 161 patients with invasive MCN, median overall survival (OS) was 133 months and 45% of patients received adjuvant therapy. Multivariable analysis demonstrated that poorly differentiated tumors [odds ratio (OR) 4.19, 95% confidence interval (CI) 1.47-11.98; p = 0.008] and positive lymph node status (OR 2.67, 95% CI 1.02-6.98; p = 0.042) were independent predictors of receiving adjuvant therapy. Lymph node positivity [hazard ratio (HR) 2.90, 95% CI 1.47-5.73; p = 0.002], positive margins (HR 5.28, 95% CI 2.28-12.27; p

BACKGROUND: In 2023 alone, its estimated that over 64,000 patients will be diagnosed with PDAC and more than 50,000 patients will die of the disease. Current guidelines recommend neoadjuvant therapy for patients with borderline resectable and locally advanced PDAC, and data is emerging on its role in resectable disease. Neoadjuvant chemotherapy may increase the number of patients able to receive complete chemotherapy regimens, increase the rate of microscopically tumor-free resection (R0) margin, and aide in identifying unfavorable tumor biology. To date, this is the largest study to examine surgical outcomes after long-duration neoadjuvant chemotherapy for PDAC. METHODS: Retrospective analysis of single-institution data. RESULTS: The routine use of long-duration therapy in our study (median cycles: FOLFIRINOX = 10; gemcitabine-based = 7) is unique. The majority (85%) of patients received FOLFIRINOX without radiation therapy; the R0 resection rate was 76%. Median OS was 41 months and did not differ significantly among patients with resectable, borderline-resectable, or locally advanced disease. CONCLUSIONS: This study demonstrates that in patients who undergo surgical resection after receipt of long-duration neoadjuvant FOLFIRINOX therapy alone, survival outcomes are similar regardless of pretreatment resectability status and that favorable surgical outcomes can be attained.

Myeloperoxidase (MPO), oxidative stress (OS), and endoplasmic reticulum (ER) stress are increased in the lungs of rat pups raised in hyperoxia, an established model of bronchopulmonary dysplasia (BPD). However, the relationship between OS, MPO, and ER stress has not been examined in hyperoxia rat pups. We treated Sprague-Dawley rat pups with tunicamycin or hyperoxia to determine this relationship. ER stress was detected using immunofluorescence, transcriptomic, proteomic, and electron microscopic analyses. Immunofluorescence observed increased ER stress in the lungs of hyperoxic rat BPD and human BPD. Proteomic and morphometric studies showed that tunicamycin directly increased ER stress of rat lungs and decreased lung complexity with a BPD phenotype. Previously, we showed that hyperoxia initiates a cycle of destruction that we hypothesized starts from increasing OS through MPO accumulation and then increases ER stress to cause BPD. To inhibit ER stress, we used tauroursodeoxycholic acid (TUDCA), a molecular chaperone. To break the cycle of destruction and reduce OS and MPO, we used N-acetyl-lysyltyrosylcysteine amide (KYC). The fact that TUDCA improved lung complexity in tunicamycin- and hyperoxia-treated rat pups supports the idea that ER stress plays a causal role in BPD. Additional support comes from data showing TUDCA decreased lung myeloid cells and MPO levels in the lungs of tunicamycin- and hyperoxia-treated rat pups. These data link OS and MPO to ER stress in the mechanisms mediating BPD. KYC's inhibition of ER stress in the tunicamycin-treated rat pup's lung provides additional support for the idea that MPO-induced ER stress plays a causal role in the BPD phenotype. ER stress appears to expand our proposed cycle of destruction. Our results suggest ER stress evolves from OS and MPO to increase neonatal lung injury and impair growth and development. The encouraging effect of TUDCA indicates that this compound has the potential for treating BPD.

Pancreatoblastoma is perceived to be aggressive in adults; however, data are limited due to the rarity of the disease. We benchmarked clinico-pathologic characteristics, outcomes, and survival of adult patients with pancreatoblastoma to a comparable PDAC cohort using the National Cancer Database (NCDB). This study included 301,204 patients: 35 with pancreatoblastoma and 301,169 PDAC patients. Pancreatoblastoma patients were younger than PDAC patients (56 vs. 69 years, p < 0.001). More pancreatoblastoma patients were managed at academic institutions (63.0% vs. 40.7%, p = 0.047). The most frequent primary site was the head and the neck of the pancreas. There were no differences in tumor size (4.2 cm vs. 3.7 cm, p = 0.828), lymph node positivity (14.3% vs. 26.4%, p = 0.103), or metastasis at time of diagnosis (31.4% vs. 46.1%, p = 0.081). The majority of pancreatoblastoma patients underwent resection compared to a minority of PDAC patients (69.7% vs. 15.5%, p < 0.001). Time from diagnosis to surgery was longer for pancreatoblastoma patients (33 vs. 14 days, p = 0.030). Pancreaticoduodenectomy was the most common type of resection in the pancreatoblastoma and PDAC groups (47.8% vs. 67.7%, p = 0.124). Among resected patients, pancreatoblastoma patients were less likely to receive radiation (4.8% vs. 37.0%, p = 0.002), but the use of chemotherapy was similar to PDAC patients (60.9% vs. 70.7%). After matching, median overall survival was longer for pancreatoblastoma than PDAC (59.8 months vs. 15.2 months, p = 0.014).

Background NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide) is a prognostic biomarker in heart failure (HF) with reduced ejection fraction. However, it is unclear whether there is a sex difference in NT‐proBNP response and whether the therapeutic goal of NT‐proBNP ≤1000 pg/mL has equivalent prognostic value in men and women with HF with reduced ejection fraction. Methods and Results In a secondary analysis of the GUIDE‐IT (Guiding Evidence Based Therapy Using Biomarker Intensified Treatment) trial we analyzed trends in NT‐proBNP and goal attainment by sex. Differences in clinical characteristics, HF treatment, and time to all‐cause death or HF hospitalization were compared. Landmark analysis at 3 months determined the prognostic value of early NT‐proBNP goal achievement in men and women. Of the 286 (32%) women and 608 (68%) men in the GUIDE‐IT trial, women were more likely to have a nonischemic cause and shorter duration of HF. Guideline‐directed medical therapy was less intense over time in women. The absolute NT‐proBNP values were consistently lower in women; however, the change in NT‐proBNP and clinical outcomes were similar. After adjustment, women achieving the NT‐proBNP goal had an 82% reduction in death or HF hospitalization compared with a 59% reduction in men. Conclusions Men and women with HF with reduced ejection fraction had a similar NT‐proBNP response despite less intensive HF treatment among women. However, compared with men, the early NT‐proBNP goal of ≤1000 pg/mL had greater prognostic value in women. Future efforts should be aimed at intensifying guideline‐directed medical therapy in women, which may result in greater NT‐proBNP reductions and improved outcomes in women with HF with reduced ejection fraction. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01685840.

BackgroundAllergic contact dermatitis (ACD) is a common skin disorder affecting an estimated 15-20% of the general population. The mouse model of ACD is contact hypersensitivity (CHS), which consists of two phases: induction and elicitation. Although neutrophils are required for both CHS disease phases their mechanisms of action are poorly understood. Neutrophils release myeloperoxidase (MPO) that through oxidation of biomolecules leads to cellular damage.ObjectivesThis study investigated mechanisms whereby MPO contributes to CHS pathogenesis.MethodsCHS was induced in mice using oxazolone (OX) as the initiating hapten applied to the skin. After 7 days, CHS was elicited by application of OX to the ear and disease severity was measured by ear thickness and vascular permeability in the ear. The role of MPO in the two phases of CHS was determined utilizing MPO-deficient mice and a specific MPO inhibitor.ResultsDuring the CHS induction phase MPO-deficiency lead to a reduction in IL-1β production in the skin and a subsequent reduction in migratory dendritic cells (DC) and effector T cells in the draining lymph node. During the elicitation phase, inhibition of MPO significantly reduced both ear swelling and vascular permeability.ConclusionMPO plays dual roles in CHS pathogenesis. In the initiation phase MPO promotes IL-1β production in the skin and activation of migratory DC that promote effector T cell priming. In the elicitation phase MPO drives vascular permeability contributing to inflammation. These results indicate that MPO it could be a potential therapeutic target for the treatment of ACD in humans.

Plaque psoriasis is a common inflammatory condition of the skin characterized by red, flaking lesions. Current therapies for plaque psoriasis target many facets of the autoimmune response, but there is an incomplete understanding of how oxidative damage produced by enzymes such as myeloperoxidase contributes to skin pathology. In this study, we used the Aldara (Imiquimod) cream model of plaque psoriasis in mice to assess myeloperoxidase inhibition for treating psoriatic skin lesions. To assess skin inflammation severity, an innovative mouse psoriasis scoring system was developed. We found that myeloperoxidase inhibition ameliorated psoriasis severity when administered either systemically or topically. The findings of this study support the role of oxidative damage in plaque psoriasis pathology and present potential new therapeutic avenues for further exploration.

PURPOSE: We aimed to examine the impact of different conference formats (in-person, virtual, and hybrid) of the ASCO conference on greenhouse gas (GHG) emissions and to recommend sustainable options for future conferences. MATERIALS AND METHODS: This study used data on the number of attendees, their departure locations, and the type of attendance (in-person v virtual) provided by ASCO between 2019 and 2022. The GHG emissions resulting from air and ground travel, remote connectivity, conference space utilization, hotel stays, distributed conference materials, and electricity use were estimated for each year. Emissions were stratified by attendee country of origin, type of attendance, and year. Simulations were conducted to evaluate how changes in conference size, location, and format impact emissions, as well as estimate the resulting mitigations from adopting the proposed changes. RESULTS: The highest estimated GHG emissions, calculated in carbon dioxide equivalents (CO2e), were associated with the 2019 in-person conference (37,251 metric tons of CO2e). Although international attendees had the largest contribution to emissions in all years (>50%), location optimization models, which selected conference locations that most minimized GHG emissions, yielded only minimal reductions (approximately 3%). Simulations examining changes to the conference format, location, and attendance percentage suggested that hub-and-spoke, where multiple conference locations are selected by global region, or hybrid models, with both in-person and virtual components, are likely to cause the largest drops in emissions (up to 86%). CONCLUSION: Using historical conference data, this study identifies key aspects that can be modified to reduce emissions and consequently promote more sustainable and equitable conference attendance. Hybrid conferences may be the best solution to maintain the networking opportunities provided by conferences while balancing out their environmental footprint.

BACKGROUND: Tebentafusp, a T-cell receptor-bispecific molecule that targets glycoprotein 100 and CD3, is approved for adult patients who are positive for HLA-A*02:01 and have unresectable or metastatic uveal melanoma. The primary analysis in the present phase 3 trial supported a long-term survival benefit associated with the drug. METHODS: We report the 3-year efficacy and safety results from our open-label, phase 3 trial in which HLA-A*02:01-positive patients with previously untreated metastatic uveal melanoma were randomly assigned in a 2:1 ratio to receive tebentafusp (tebentafusp group) or the investigators choice of therapy with pembrolizumab, ipilimumab, or dacarbazine (control group), with randomization stratified according to the lactate dehydrogenase level. The primary end point was overall survival. RESULTS: At a minimum follow-up of 36 months, median overall survival was 21.6 months in the tebentafusp group and 16.9 months in the control group (hazard ratio for death, 0.68; 95% confidence interval, 0.54 to 0.87). The estimated percentage of patients surviving at 3 years was 27% in the tebentafusp group and 18% in the control group. The most common treatment-related adverse events of any grade in the tebentafusp group were rash (83%), pyrexia (76%), pruritus (70%), and hypotension (38%). Most tebentafusp-related adverse events occurred early during treatment, and no new adverse events were observed with long-term administration. The percentage of patients who discontinued treatment because of adverse events continued to be low in both treatment groups (2% in the tebentafusp group and 5% in the control group). No treatment-related deaths occurred. CONCLUSIONS: This 3-year analysis supported a continued long-term benefit of tebentafusp for overall survival among adult HLA-A*02:01-positive patients with previously untreated metastatic uveal melanoma. (Funded by Immunocore; IMCgp100-202 ClinicalTrials.gov number, NCT03070392; EudraCT number, 2015-003153-18.).

The purpose of this article is to illustrate the work that has resulted from a collaboration between a biology professor, a school psychology professor, a researcher in higher education access, and the writing programs director. The essential school psychologist role, as classroom observer and data analyzer, is discussed through an example of work done as part of a larger project focusing on student success and retention for at-risk populations in introductory college biology courses. Best practices for consulting at the college level are discussed and include: collaborate to cultivate the willing, collect and analyze data to sustain instructor involvement, and communicate and advocate. We hope that the model exemplified here might inspire future interdisciplinary collaborations that draw on school psychology expertise to design and conduct research.

In response to calls for pedagogical reforms in undergraduate biology courses to decrease student attrition rates and increase active learning, this article describes one faculty member’s conversion from traditional teaching methods to more engaging forms of practice. Partially told as a narrative, this article illustrates a.) the way many faculty initially learn to teach by modeling the pedagogy from their own undergraduate programs; b.) the kind of support biology faculty may need to break out of traditional molds; c.) how writing can promote active learning; and d.) the impact of reformed pedagogy on student levels of engagement. The latter will be demonstrated through assessment results gathered from student surveys, reflective writing, and focus group interview. Ultimately, the study challenges misunderstandings some faculty might have regarding the value of writing in science classes and offers inspiration, urging critical reflection and persistence.

Introductory biology courses are supposed to serve as gateways for many majors, but too often they serve instead as gatekeepers. Reliance on lectures, large classes, and multiple-choice tests results in high drop and failure rates. Critiques of undergraduate science education are clear about the problems with conventional introductory science courses, and yet the problems persist. As David Hanauer and Cynthia Bauerle explain, "Given the potential for science to address important problems, undergraduate programs ought to be functioning as busy portals for engaging students' innate fascination and developing their understanding of the nature and practice of science. Instead, recent studies suggest, the opposite is true: over half of the students who enter college with an interest in science do not persist in their training beyond the first year or two of introductory coursework." Researchers and expert practitioners have long proposed using student-centered, active learning strategies to improve engagement, learning, and achievement. Others have documented the ways class size is important for student-centered pedagogy. Following Hanauer and Bauerle, who recommend using assessment reform to facilitate such curricular innovations, the authors contend that the better the assessment and the more focused the guidance provided to the instructor, the greater the leverage. This article presents findings from a pilot study suggesting that authentic assessment embedded in best teaching practices can show what kind of change is needed. The study allowed the authors to observe the relative impacts of both class size and the use of writing as an assessment strategy, and thus to identify the sequence reform efforts must take. The purposes of this article are, first, to report on the experience responding to Hanauer and Bauerle's call, and second, to identify the key components that gave that "reform lever" additional power: the careful selection and preliminary testing of essay questions requiring critical thinking, the reduced size of one section of an entry-level biology course, the support of a networked improvement community, and guidance for the instructor during the testing of new methods

Clicker questions are a commonly used active learning technique that stimulates student interactions to help advance understanding of key concepts. Clicker questions are often administered with an initial vote, peer discussion, and a second vote, followed by broader classroom explanation. While clickers can promote learning, some studies have questioned whether students maintain this performance on later exams, highlighting the need to further understand how student answer patterns relate to their understanding of the material and to identify ways for clickers to benefit a broader range of students. Systematic requizzing of concepts during at-home assignments represents a promising mechanism to improve student learning. Thus, we paired clicker questions with at-home follow-up reflections to help students articulate and synthesize their understandings. This pairing of clickers with homework allowed us to decipher how student answer patterns related to their underlying conceptions and to determine if revisiting concepts provided additional benefits. We found that students answering both clicker votes correctly performed better on isomorphic exam questions and that students who corrected their answers after the first vote did not show better homework or exam performance than students who maintained an incorrect answer across both votes. Furthermore, completing the follow-up homework assignment modestly boosted exam question performance. Our data suggest that longer-term benefits of clickers and associated homework may stem from students having repeated opportunities to retrieve, refine, and reinforce emerging conceptions.

Myeloperoxidase (MPO) plays important roles in disease by increasing oxidative and nitrosative stress and oxidizing lipoproteins. Here we report N-acetyl lysyltyrosylcysteine amide (KYC) is an effective inhibitor of MPO activity. We show KYC inhibits MPO-mediated hypochlorous acid (HOCl) formation and nitration/oxidation of LDL. Disulfide is the major product of MPO-mediated KYC oxidation. KYC (⩽4,000 μM) does not induce cytotoxicity in bovine aortic endothelial cells (BAECs). KYC inhibits HOCl generation by phorbol myristate acetate (PMA)-stimulated neutrophils and human promyelocytic leukemia (HL-60) cells but not superoxide generation by PMA-stimulated HL-60 cells. KYC inhibits MPO-mediated HOCl formation in BAEC culture and protects BAECs from MPO-induced injury. KYC inhibits MPO-mediated lipid peroxidation of LDL whereas tyrosine (Tyr) and tryptophan (Trp) enhance oxidation. KYC is unique as its isomers do not inhibit MPO activity, or are much less effective. Ultraviolet-visible spectral studies indicate KYC binds to the active site of MPO and reacts with compounds I and II. Docking studies show the Tyr of KYC rests just above the heme of MPO. Interestingly, KYC increases MPO-dependent H2O2 consumption. These data indicate KYC is a novel and specific inhibitor of MPO activity that is nontoxic to endothelial cell cultures. Accordingly, KYC may be useful for treating MPO-mediated vascular disease.

Activated leukocytes and polymorphonuclear neutrophils (PMN) release myeloperoxidase (MPO), which binds to endothelial cells (EC), is translocated, and generates oxidants that scavenge nitric oxide (NO) and impair EC function. To determine whether MPO impairs EC function in sickle cell disease (SCD), control (AA) and SCD mice were treated with N-acetyl-lysyltyrosylcysteine-amide (KYC). SCD humans and mice have high plasma MPO and soluble L-selectin (sL-selectin). KYC had no effect on MPO but decreased plasma sL-selectin and malondialdehyde in SCD mice. MPO and 3-chlorotyrosine (3-ClTyr) were increased in SCD aortas. KYC decreased MPO and 3-ClTyr in SCD aortas to the levels in AA aortas. Vasodilatation in SCD mice was impaired. KYC increased vasodilatation in SCD mice more than 2-fold, to ∼60% of levels in AA mice. KYC inhibited MPO-dependent 3-ClTyr formation in EC proteins. SCD mice had high plasma alanine transaminase (ALT), which tended to decrease in KYC-treated SCD mice (P = 0.07). KYC increased MPO and XO/XDH and decreased 3-ClTyr and 3-nitrotyrosine (3-NO2Tyr) in SCD livers. These data support the hypothesis that SCD increases release of MPO, which generates oxidants that impair EC function and injure livers. Inhibiting MPO is an effective strategy for decreasing oxidative stress and liver injury and restoring EC function in SCD.