Research Progress on CARM1 and its Relationship with Colorectal Cancer.

Coactivator-associated arginine methyltransferase 1 (CARM1) is significant as a key member of the PRMT family, crucial for regulating arginine methylation, and its association with colorectal cancer underscores its potential as a therapeutic target. Consequently, CARM1 inhibitors have emerged as potential therapeutic agents in cancer treatment and valuable chemical tools for cancer research. Despite steady progress in CARM1 inhibitor research, challenges persist in discovering effective, isoform-selective, cell-permeable, and in vivo-active CARM1 inhibitors for colorectal cancer. This review summarizes the research progress on CARM1 and its relationship with colorectal cancer, aiming to provide a theoretical basis for the radiotherapy of colorectal cancer.

SQLE-a promising prognostic biomarker in cervical cancer: implications for tumor malignant behavior, cholesterol synthesis, epithelial-mesenchymal transition, and immune infiltration.

BACKGROUND: Cervical cancer, encompassing squamous cell carcinoma and endocervical adenocarcinoma (CESC), presents a considerable risk to the well-being of women. Recent studies have reported that squalene epoxidase (SQLE) is overexpressed in several cancers, which contributes to cancer development. METHODS: RNA sequencing data for SQLE were obtained from The Cancer Genome Atlas. In vitro experiments, including colorimetry, colony formation, Transwell, RT-qPCR, and Western blotting were performed. Furthermore, a transplanted CESC nude mouse model was constructed to validate the tumorigenic activity of SQLE in vivo. Associations among the SQLE expression profiles, differentially expressed genes (DEGs), immune infiltration, and chemosensitivity were examined. The prognostic value of genetic changes and DNA methylation in SQLE were also assessed. RESULTS: SQLE mRNA expression was significantly increased in CESC. ROC analysis revealed the strong diagnostic ability of SQLE toward CESC. Patients with high SQLE expression experienced shorter overall survival. The promotional effects of SQLE on cancer cell proliferation, metastasis, cholesterol synthesis, and EMT were emphasized. DEGs functional enrichment analysis revealed the signaling pathways and biological processes. Notably, a connection existed between the SQLE expression and the presence of immune cells as well as the activation of immune checkpoints. Increased SQLE expressions exhibited increased chemotherapeutic responses. SQLE methylation status was significantly associated with CESC prognosis. CONCLUSION: SQLE significantly affects CESC prognosis, malignant behavior, cholesterol synthesis, EMT, and immune infiltration; thereby offering diagnostic and indicator roles in CESC. Thus, SQLE can be a novel therapeutic target in CESC treatment.

BioCaster in 2021: automatic disease outbreaks detection from global news media.

SUMMARY: BioCaster was launched in 2008 to provide an ontology-based text mining system for early disease detection from open news sources. Following a 6-year break, we have re-launched the system in 2021. Our goal is to systematically upgrade the methodology using state-of-the-art neural network language models, whilst retaining the original benefits that the system provided in terms of logical reasoning and automated early detection of infectious disease outbreaks. Here, we present recent extensions such as neural machine translation in 10 languages, neural classification of disease outbreak reports and a new cloud-based visualization dashboard. Furthermore, we discuss our vision for further improvements, including combining risk assessment with event semantics and assessing the risk of outbreaks with multi-granularity. We hope that these efforts will benefit the global public health community. AVAILABILITY AND IMPLEMENTATION: BioCaster web-portal is freely accessible at http://biocaster.org.

KLK5 is associated with the radioresistance, aggression, and progression of cervical cancer.

OBJECTIVE: The role of kallikrein-related peptidase 5 (KLK5) has been studied in several diseases, including skin and ovarian cancers. However, its role in cervical cancer remains unclear, particularly in regulating the radiation resistance and growth of cervical cancer cells. Radiation resistance of cervical cancer is associated with local recurrence, distant metastasis, and reduced survival. METHODS: We first analyzed radiotherapy-naive samples and relevant clinical data from patients with cervical cancer who received radiotherapy without surgery or other antitumor treatment from 2014 to 2016. Subsequently, biopsied tissues, in vitro cells, and transplanted tumors in nude mice were investigated. RESULTS: Gene sequencing and clinical data analysis showed that KLK5 overexpression was associated with a poor prognosis post-radiotherapy. In in vitro cell and tumor transplantation experiments, KLK5 overexpression significantly increased radiation resistance. However, downregulating KLK5 expression increased radiosensitivity. CONCLUSION: Our results confirm that KLK5 is vital to the radioresistance of cervical cancer, and provide a new target and marker for the treatment of radioresistance in cervical cancer.

Matrix stiffness regulates macrophage polarization in atherosclerosis.

Atherosclerosis is a chronic inflammatory disease and the pathological basis of many fatal cardiovascular diseases. Macrophages, the main inflammatory cells in atherosclerotic plaque, have a paradox role in disease progression. In response to different microenvironments, macrophages mainly have two polarized directions: pro-inflammatory macrophages and anti-inflammatory macrophages. More and more evidence shows that macrophage is mechanosensitive and matrix stiffness regulate macrophage phenotypes in atherosclerosis. However, the molecular mechanism of matrix stiffness regulating macrophage polarization still lacks in-depth research, which hinders the development of new anti-atherosclerotic therapies. In this review, we discuss the important role of matrix stiffness in regulating macrophage polarization through mechanical signal transduction (Hippo, Piezo, cytoskeleton, and integrin) and epigenetic mechanisms (miRNA, DNA methylation, and histone). We hope to provide a new perspective for atherosclerosis therapy by targeting matrix stiffness and macrophage polarization.

Substantial increase in detection efficiency for filter array-based spectral sensors.

A method that significantly increases the detection efficiency of filter array-based spectral sensors is proposed. The basic concept involves a wavelength-dependent redistribution of incident light before it reaches the filter elements located in front of the detector. Due to this redistribution, each filter element of the array receives a spatially concentrated amount of a pre-selected and adjusted spectral partition of the entire incident light. This approach can be employed to significantly reduce the reflection and absorption losses of each filter element. The proof-of-concept is demonstrated by a setup that combines a series of consecutively arranged dichroic filters with Fabry-Perot filter arrays. Experimentally, an efficiency increase by a factor larger than 4 compared to a reference system is demonstrated. The optical system is a non-imaging spectrometer, which combines the efficiency enhancement module with the filter arrays, is compact (17.5mm×17.5mm×7.8mm), and integrated completely inside the CCD camera mount.

Development of a Framework for Establishing 'Gold Standard' Outbreak Data from Submitted SARS-CoV-2 Genome Samples.

Submitted genomic data for respiratory viruses reflect the emergence and spread of new variants. Although delays in submission limit the utility of these data for prospective surveillance, they may be useful for evaluating other surveillance sources. However, few studies have investigated the use of these data for evaluating aberration detection in surveillance systems. Our study used a Bayesian online change point detection algorithm (BOCP) to detect increases in the number of submitted genome samples as a means of establishing 'gold standard' dates of outbreak onset in multiple countries. We compared models using different data transformations and parameter values. BOCP detected change points that were not sensitive to different parameter settings. We also found data transformations were essential prior to change point detection. Our study presents a framework for using global genomic submission data to develop 'gold standard' dates about the onset of outbreaks due to new viral variants.

SGLT1 inhibition alleviates radiation-induced intestinal damage through promoting mitochondrial homeostasis.

Radiation-induced intestinal injury (RIII) constitutes a challenge in radiotherapy. Ionizing radiation (IR) induces DNA and mitochondrial damage by increasing reactive oxygen species (ROS). Sodium-glucose cotransporter 1 (SGLT1) is abundant in the gastrointestinal tract and the protective effects of inhibited SGLT1 in kidney and cardiovascular disease have been widely reported. However, the function of SGLT1 in RIII remains unclear. Herein, we reported that IR induced intestinal epithelial cell damage along with upregulation of SGLT1 in vivo and in vitro, which was alleviated by inhibition of SGLT1. Specifically, maintaining intestinal cell homeostasis was detected through cellular proliferation, apoptosis, and DNA damage assays, promoting epithelial regeneration and lifespan extension. Considering the importance of mitochondrial function in cell fate, we next confirmed that SGLT inhibition maintains mitochondrial homeostasis through enhanced mitophagy in intestinal epithelial cells. Finally, based on the bioinformatics analysis and cell validation, we demonstrated that inhibition of SGLT1 suppresses the PI3K/AKT/mTOR pathway to enhance mitophagy activation post-irradiation. In addition, we preliminarily demonstrate that SGLT inhibitors do not affect the radiosensitivity of tumors. Hence, our findings suggest that inhibition of SGLT is a promising therapeutic strategy to protect against RIII. To the best of our knowledge, this is the first report on the potential effect of SGLT1 inhibition in RIII.

Radiation-induced YAP/TEAD4 binding confers non-small cell lung cancer radioresistance via promoting NRP1 transcription.

Despite the importance of radiation therapy as a non-surgical treatment for non-small cell lung cancer (NSCLC), radiation resistance has always been a concern, due to poor patient response and prognosis. Therefore, it is crucial to uncover novel targets to enhance radiotherapy and investigate the mechanisms underlying radiation resistance. Previously, we demonstrated that NRP1 was connected to radiation resistance in NSCLC cells. In the present study, bioinformatics analysis of constructed radiation-resistant A549 and H1299 cell models revealed that transcription coactivator YAP is a significant factor in cell proliferation and metastasis. However, there has been no evidence linking YAP and NRP1 to date. In this research, we have observed that YAP contributes to radiation resistance in NSCLC cells by stimulating cell proliferation, migration, and invasion. Mechanistically, YAP dephosphorylation after NSCLC cell radiation. YAP acts as a transcription co-activator by binding to the transcription factor TEAD4, facilitating TEAD4 to bind to the NRP1 promoter region and thereby increasing NRP1 expression. NRP1 has been identified as a new target gene for YAP/TEAD4. Notably, when inhibiting YAP binds to TEAD4, it inhibits NRP1 expression, and Rescue experiments show that YAP/TEAD4 influences NRP1 to regulate cell proliferation, metastasis and leading to radiation resistance generation. According to these results, YAP/TEAD4/NRP1 is a significant mechanism for radioresistance and can be utilized as a target for enhancing radiotherapy efficacy.

Long-Term Safety and Efficacy Evaluation of Travoprost Intracameral Implant Based on Pooled Analyses from Two Phase III Trials.

AIM: The purpose of this study was to conduct and interpret a pooled 12-month analysis of two prospective, multi-center, randomized, double-masked, controlled trials designed to assess the efficacy and safety of the travoprost intracameral implant (slow-eluting [SE] implant in development as a new therapeutic and fast-eluting [FE] implant included for masking purposes) in subjects with open-angle glaucoma (OAG) or ocular hypertension (OHT). METHODS: Subjects with OAG or OHT, on 0-3 intraocular pressure (IOP)-lowering medications, baseline unmedicated mean diurnal IOP of ≥ 21 mmHg, and IOP ≤ 36 mmHg at each baseline diurnal timepoint, received either a travoprost implant and twice-daily (BID) placebo eye drops or BID timolol 0.5% eye drops and a sham procedure. Subjects were followed through 12 months and assessed for IOP, reduction in topical IOP-lowering medications, and safety parameters including treatment-emergent adverse events (TEAEs). IOP at 8AM was prospectively collected at all study visits through 12 months and diurnal IOP, measured at 8AM, 10AM, and 4PM, was prospectively collected at baseline, day 10, week 6, and months 3 and 12. RESULTS: A total of 1150 subjects were randomized (385 FE implant, 380 SE implant, and 385 sham/timolol) across the two trials. Statistical non-inferiority to timolol and clinically relevant reductions in 8AM IOPs were demonstrated at month 12. In more detail, both implant groups demonstrated statistical non-inferiority to timolol and clinically relevant reductions from baseline in mean diurnal IOP at all visits over the 12-month evaluation period when diurnal IOP was collected. Additionally, both implant groups demonstrated robust treatment effect based on 8AM average IOP from day 10 through the specified visit which ranged from day 10 to month 12 from 6.9 to 8.5 mmHg in the FE implant group; 6.8 to 8.5 mmHg in the SE implant group; and 7.3 to 7.5 mmHg in the sham/timolol group. With regards to reduction in topical pharmacotherapy, at month 12, 77.6% of FE and 81.4% of SE implant eyes were completely free of all topical IOP-lowering medications and a significantly greater proportion of FE and SE implant eyes (89.9% and 93.0%) versus sham/timolol eyes (66.9%) were on the same or fewer topical IOP-lowering medications compared with pre-study (p <  0.0001). Furthermore, of subjects on topical IOP medications at screening, a significantly greater proportion of FE implant (80.2%) and SE implant (85.1%) eyes versus sham/timolol (22.8%) eyes were on fewer topical IOP-lowering medications at month 12 compared with pre-study (p <  0.0001). Lastly, of SE implant eyes on same or fewer topical IOP-lowering medications at month 12, the average through month 12 decreased by 0.9 medications, and of those SE implant eyes on fewer topical IOP-lowering medications compared with pre-study, the average through month 12 decreased by 1.4 medications. The most common TEAEs related to study treatment were hyperemia (conjunctival or ocular), iritis, and IOP increased. CONCLUSION: The travoprost intracameral implant demonstrated robust IOP-lowering efficacy that was sustained and statistically non-inferior to timolol over the entire 12 months, resulting in a significant reduction in topical IOP-lowering medication use, with the majority of SE implant eyes remaining completely free of all topical IOP-lowering medications. In addition, the implant demonstrated a favorable safety and tolerability profile based on this pooled 12-month analysis of two pivotal trials. TRIAL REGISTRATION: ClinicalTrials.gov identifiers NCT03519386 (registered May 09, 2018) and NCT03868124 (registered March 08, 2019).

Effects and potential mechanisms of IGF1/IGF1R in the liver fibrosis: A review.

Liver fibrosis is a wound-healing response due to persistent liver damage and it may progress to cirrhosis and even liver cancer if no intervention is given. In the current cognition, liver fibrosis is reversible. So, it is of great significance to explore the related gene targets or biomarker for anti-fibrosis of liver. Insulin like growth factor 1 (IGF1) and IGF1 receptor (IGF1R) are mainly expressed in the liver tissues and play critical roles in the liver function. The present review summarized the role of IGF1/IGF1R and its signaling system in liver fibrosis and illustrated the potential mechanisms including DNA damage repair, cell senescence, lipid metabolism and oxidative stress that may be involved in this process according to the studies on the fibrosis of liver or other organs. In particular, the roles of IGF1 and IGF1R in DNA damage repair were elaborated, including membrane-localized and nucleus-localized IGF1R. In addition, for each of the potential mechanism in anti-fibrosis of liver, the signaling pathways of the IGF1/IGF1R mediated and the cell species in liver acted by IGF1 and IGF1R under different conditions were included. The data in this review will support for the study about the effect of IGF1/IGF1R on liver fibrosis induced by various factors, meanwhile, provide a basis for the study of liver fibrosis to focus on the communications between the different kinds of liver cells.

One Stone, Three Birds: Multifunctional Nanodots as "Pilot Light" for Guiding Surgery, Enhanced Radiotherapy, and Brachytherapy of Tumors.

Surgery, radiotherapy (RT), and brachytherapy are crucial treatments for localized deep tumors. However, imprecise tumor location often leads to issues such as positive surgical margins, extended radiotherapy target volumes, and radiation damage to healthy tissues. Reducing side effects in healthy tissue and enhancing RT efficacy are critical challenges. To address these issues, we developed a multifunctional theranostic platform using Au/Ag nanodots (Au/AgNDs) that act as a "pilot light" for real-time guided surgery, high-efficiency RT, and brachytherapy, achieving a strategy of killing three birds with one stone. First, dual-mode imaging of Au/AgNDs enabled precision RT, minimizing damage to adjacent normal tissue during X-ray irradiation. Au/AgNDs enhanced ionizing radiation energy deposition, increased intracellular reactive oxygen species (ROS) generation, regulated the cell cycle, promoted DNA damage formation, and inhibited DNA repair in tumor cells, significantly improving RT efficacy. Second, in brachytherapy, precise guidance provided by dual-mode imaging addressed challenges related to non-visualization of existing interstitial brachytherapy and multiple adjustments of insertion needle positions. Meanwhile, the effect of brachytherapy was improved. Third, the excellent fluorescence imaging of Au/AgNDs accurately distinguished tumors from normal tissue, facilitating their use as a powerful tool for assisting surgeons during tumor resection. Taken together, our multifunctional theranostic platform offers real-time guidance for surgery and high-efficiency RT, and improves brachytherapy precision, providing a novel strategy and vision for the clinical diagnosis and treatment of cancer.

SIRT1 interacts with and protects glyceraldehyde-3-phosphate dehydrogenase (GAPDH) from nuclear translocation: implications for cell survival after irradiation.

Upon apoptotic stimulation, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a cytosolic enzyme normally active in glycolysis, translocates into the nucleus and activates an apoptotic cascade therein. In the present work, we show that SIRT1 prevents nuclear translocation of GAPDH via interaction with GAPDH. SIRT1 depletion triggered nuclear translocation of cytosolic GAPDH even in the absence of apoptotic stress. Such translocation was not, however, observed when SIRT1 enzymatic activity was inhibited, indicating that SIRT1 protein per se, rather than the deacetylase activity of the protein, is required to inhibit GAPDH translocation. Upon irradiation, SIRT1 prevented irradiation-induced nuclear translocation of GAPDH, accompanied by interaction of SIRT1 and GAPDH. Thus, SIRT1 functions to retain GAPDH in the cytosol, protecting the enzyme from nuclear translocation via interaction with these two proteins. This serves as a mechanism whereby SIRT1 regulates cell survival upon induction of apoptotic stress by means that include irradiation.

A Conceptual Framework for Representing Events Under Public Health Surveillance.

Information integration across multiple event-based surveillance (EBS) systems has been shown to improve global disease surveillance in experimental settings. In practice, however, integration does not occur due to the lack of a common conceptual framework for encoding data within EBS systems. We aim to address this gap by proposing a candidate conceptual framework for representing events and related concepts in the domain of public health surveillance.

GATA3 Exerts Distinct Transcriptional Functions to Regulate Radiation Resistance in A549 and H1299 Cells.

Background: Radiation resistance of lung cancer cells is a vital factor affecting the curative effect of lung cancer. Transcription factor GATA3 is involved in cell proliferation, invasion, and migration and is significantly expressed in a variety of malignancies. However, the molecular mechanism governing GATA3 regulation in lung cancer cells' radiation resistance is unknown. Methods: Radiation-resistant cell models (A549-RR and H1299-RR) were made using fractionated high-dose irradiation. Use clone formation, CCK-8, F-actin staining, cell cycle detection, and other experiments to verify whether the model is successfully constructed. Cells were transiently transfected with knockdown or overexpression plasmid. To explore the relationship between GATA3/H3K4me3 and target genes, we used ChIP-qPCR, ChIP-seq, and dual luciferase reporter gene experiments. Xenograft tumor models were used to evaluate the effect of GATA3 depletion on the tumorigenic behavior of lung cancer cells. Results: We report that transcription factors GATA3 and H3K4me3 coactivate NRP1 gene transcription when A549 cells develop radiation resistance. However, the mechanism of radiation resistance in H1299 cells is that GATA3 acts as a transcription inhibitor. The decrease of GATA3 will promote the increase of NRP1 transcription, in which H3K4me3 does not play a leading role. Conclusions: GATA3, an upstream transcriptional regulator of NRP1 gene, regulates the radioresistance of A549 and H1299 cells by opposite mechanisms, which provides a new target for radiotherapy of lung cancer.

Analysis of risk factors for mental health problems of inpatients with chronic liver disease and nursing strategies: A single center descriptive study.

The number of patients with chronic liver disease (CLD) is large. The social and economic burdens due to CLD have increased. The mental health problems of patients with CLD are prominent and deserve our attention and care. This study analyzed 320 patients with CLD who were hospitalized between January 2018 and January 2020. Questionnaire surveys were used to assess mental health status, including the Self-Rating Anxiety Scale (SAS), Self-Rating Depression Scale (SDS), and Symptom Checklist-90 (SCL-90). At the same time, basic data and potential related factors were collected. Data were analyzed using descriptive statistics and logistic regression. Among the 320 patients with CLD, 240 (75%) had mental health problems; among the total patients, education levels, occupations, course of disease, annual hospitalizations, complications, and nursing satisfaction were significantly different between the two groups (p < .05). The education levels and occupations of the group without mental health problems were significantly different within the group (p < .05). The SCL-90 found that the four factors with the highest scores were anxiety (ANX: 33.3%), depression (DEPR: 20.4%), somatization (SOM: 12.9%), and sleep and diet (SD: 9.6%). Logistic regression analysis showed that education levels, course of disease, annual hospitalizations, complications, and nursing satisfaction levels were independent risk factors for the mental health of patients with CLD. Model fitness was checked using the Hosmer-Lemeshow test. The receiver operating characteristic (ROC) curve showed that the area under the curve was 0.84. Patients with CLD have prominent mental health problems and experience many risk factors. It is necessary to adopt individualized psychological interventions and care to improve the quality of life of these patients.

Dual Characters of GH-IGF1 Signaling Pathways in Radiotherapy and Post-radiotherapy Repair of Cancers.

Radiotherapy remains one of the most important cancer treatment modalities. In the course of radiotherapy for tumor treatment, the incidental irradiation of adjacent tissues could not be completely avoided. DNA damage is one of the main factors of cell death caused by ionizing radiation, including single-strand (SSBs) and double-strand breaks (DSBs). The growth hormone-Insulin-like growth factor 1 (GH-IGF1) axis plays numerous roles in various systems by promoting cell proliferation and inhibiting apoptosis, supporting its effects in inducing the development of multiple cancers. Meanwhile, the GH-IGF1 signaling involved in DNA damage response (DDR) and DNA damage repair determines the radio-resistance of cancer cells subjected to radiotherapy and repair of adjacent tissues damaged by radiotherapy. In the present review, we firstly summarized the studies on GH-IGF1 signaling in the development of cancers. Then we discussed the adverse effect of GH-IGF1 signaling in radiotherapy to cancer cells and the favorable impact of GH-IGF1 signaling on radiation damage repair to adjacent tissues after irradiation. This review further summarized recent advances on research into the molecular mechanism of GH-IGF1 signaling pathway in these effects, expecting to specify the dual characters of GH-IGF1 signaling pathways in radiotherapy and post-radiotherapy repair of cancers, subsequently providing theoretical basis of their roles in increasing radiation sensitivity during cancer radiotherapy and repairing damage after radiotherapy.

Erratum: MicroRNA-26b suppresses autophagy in breast cancer cells by targeting DRAM1 mRNA, and is downregulated by irradiation.

[This corrects the article DOI: 10.3892/ol.2017.7452.].

The role of case importation in explaining differences in early SARS-CoV-2 transmission dynamics in Canada-A mathematical modeling study of surveillance data.

OBJECTIVE: The North American coronavirus disease-2019 (COVID-19) epidemic exhibited distinct early trajectories. In Canada, Quebec had the highest COVID-19 burden and its earlier March school break, taking place two weeks before those in other provinces, could have shaped early transmission dynamics. METHODS: We combined a semi-mechanistic model of SARS-CoV-2 transmission with detailed surveillance data from Quebec and Ontario (initially accounting for 85% of Canadian cases) to explore the impact of case importation and timing of control measures on cumulative hospitalizations. RESULTS: A total of 1544 and 1150 cases among returning travelers were laboratory-confirmed in Quebec and Ontario, respectively (symptoms onset ≤03-25-2020). Hospitalizations could have been reduced by 55% (95% CrI: 51%-59%) if no cases had been imported after Quebec's March break. However, if Quebec had experienced Ontario's number of introductions, hospitalizations would have only been reduced by 12% (95% CrI: 8%-16%). Early public health measures mitigated the epidemic spread as a one-week delay could have resulted in twice as many hospitalizations (95% CrI: 1.7-2.1). CONCLUSION: Beyond introductions, factors such as public health preparedness, responses and capacity could play a role in explaining interprovincial differences. In a context where regions are considering lifting travel restrictions, coordinated strategies and proactive measures are to be considered.

Pancrelipase delayed-release capsules (CREON) for exocrine pancreatic insufficiency due to chronic pancreatitis or pancreatic surgery: A double-blind randomized trial.

OBJECTIVES: Pancreatic-enzyme replacement therapy (PERT) is the standard of care to prevent maldigestion, malnutrition, and excessive weight loss in patients with exocrine pancreatic insufficiency (EPI) due to chronic pancreatitis (CP) or pancreatic surgery (PS). Our objective was to assess the efficacy and safety of a new formulation of pancrelipase (pancreatin) delayed-release 12,000-lipase unit capsules (CREON) in patients with EPI due to CP or PS. METHODS: This was a double-blind, randomized, multicountry, placebo-controlled, parallel-group trial enrolling patients ≥18 years old with confirmed EPI due to CP or PS conducted in clinical research centers or hospitals. After a 5-day placebo run-in period (baseline), patients were randomized to pancrelipase (72,000 lipase units per meal; 36,000 per snack) or placebo for 7 days. All patients received an individually designed diet to provide at least 100 g of fat per day. The primary efficacy measure was the change in coefficient of fat absorption (CFA) from baseline to end of the double-blind period, analyzed using non-parametric analysis of covariance. Secondary outcomes included the coefficient of nitrogen absorption (CNA), clinical symptoms, and safety parameters. RESULTS: In total, 25 patients (median age of 54 years, 76% male) received pancrelipase and 29 patients (median age of 50 years, 69% male) received placebo. Th e mean ± s.d. change from baseline in CFA was significantly greater with pancrelipase vs. placebo: 31.9 ± 18.6 vs. 8.7 ± 12.4 % ( P < 0.0001) [corrected]. Similarly, the mean ± s.d. change from baseline in CNA was greater for pancrelipase vs. placebo: 35.2 ± 29.1 vs. 8.9 ± 28.0 % ( P = 0.0005) [corrected].Greater improvements from baseline in stool frequency, stool consistency, abdominal pain, and flatulence were observed with pancrelipase vs. placebo. Treatment-emergent adverse events (TEAEs) were reported in five patients (20.0%) in the pancrelipase group and in six (20.7%) in the placebo group; the most common were gastrointestinal (GI) events and metabolism/nutrition disorders. There were no treatment discontinuations due to TEAEs. CONCLUSIONS: Pancrelipase delayed-release 12,000-lipase unit capsules were effective in treating fat and nitrogen maldigestion with a TEAE rate similar to that of placebo in patients with EPI due to CP or PS.