Pien Tze Huang Inhibits Proliferation of Colorectal Cancer Cells through Suppressing PNO1 Expression and Activating p53/p21 Signaling Pathway.

OBJECTIVE: To explore the regulatory effect of Pien Tze Huang (PZH) on targeting partner of NOB1 (PNO1) and it's down-stream mediators in colorectal cancer (CRC) cells. METHODS: Quantitative polymerase chain reaction was performed to determine mRNA levels of PNO1, TP53, and CDKN1A. Western blotting was performed to determine protein levels of PNO1, p53, and p21. HCT-8 cells were transduced with a lentivirus over-expressing PNO1. Colony formation assay was used to detect cell survival in PNO1 overexpression of HCT-8 cells after PZH treatment. Cell-cycle distribution, cell viability and cell apoptosis were performed to identify the effect of PNO1 overexpression on cell proliferation and apoptosis of HCT-8 cells after PZH treatment. Xenograft BALB/c nude mice bearing HCT116 cells transduced with sh-PNO1 or sh-Ctrl lentivirus were evaluated. Western blot assay was performed to detect PNO1, p53, p21 and PCNA expression in tumor sections. Terminal deoxynucleotidyl transferase dUTP nick end labling (TUNEL) assay was used to determine the apoptotic cells in tissues. RESULTS: PZH treatment decreased cell viability, down-regulated PNO1 expression, and up-regulated p53 and p21 expressions in HCT-8 cells (P<0.05). PNO1 overexpression attenuated the effects of PZH treatment, including the expression of p53 and p21, cell growth, cell viability, cell cycle arrest and cell apoptosis in vitro (P<0.05). PNO1 knockdown eliminated the effects of PZH treatment on tumor growth, inhibiting cell proliferation inhibition and apoptosis induction in vivo (P<0.05). Similarly, PNO1 knockdown attenuated the effects of PZH treatment on the down-regulation of PNO1 and up-regulation of p53 and p21 in vivo (P<0.05). CONCLUSION: The mechanism by which PZH induces its CRC anti-proliferative effect is at least in part by regulating the expression of PNO1 and its downstream targets p53 and p21.

Impact of Erythromycin as a Prokinetic on the Gut Microbiome in Children with Feeding Intolerance-A Pilot Study.

BACKGROUND: Studies have demonstrated that the gut microbiome changes upon exposure to systemic antibiotics. There is a paucity of literature regarding impact on the gut microbiome by long-term usage of erythromycin ethyl succinate (EES) when utilized as a prokinetic. METHODS: Stool samples from pediatric patients with feeding intolerance who received EES (N = 8) as a prokinetic were analyzed for both bacteriome and mycobiome. Age-matched children with similar clinical characteristics but without EES therapy were included as controls (N = 20). RESULTS: In both groups, Proteobacteria, Firmicutes, and Bacteroidetes were the most abundant bacterial phyla. Ascomycota was the most abundant fungal phyla, followed by Basidiomycota. There were no significant differences in richness between the groups for both bacterial and fungal microbiome. Alpha diversity (at genus and species levels) and beta diversity (at the genus level) were not significantly different between the groups for both bacterial and fungal microbiome. At the species level, there was a significant difference between the groups for fungal microbiota, with a p-value of 0.029. We also noted that many fungal microorganisms had significantly higher p-values in the EES group than controls at both genera and species levels. CONCLUSIONS: In this observational case-control study, the prokinetic use of EES was associated with changes in beta diversity between the groups for mycobiome at the species level. Many fungal microorganisms were significantly higher in the EES group when compared to the controls. Confirmation of these results in larger trials will provide further evidence regarding the impact of EES on gut microbiota when utilized as a prokinetic agent.

Natural History of Pediatric Patients With Crohn's Disease Treated With Mesalamine Therapy.

Background: 5-aminosalicylates (5-ASA) are used to treat mild to moderate ulcerative colitis. Despite their lack of efficacy in Crohn disease (CD), they are still used in real-world practice. Additionally, when patients have progressive disease, they may escalate to biologic therapy, at which time 5-ASA may or may not be discontinued. Objectives: The aim of this study is to assess the clinical outcomes of patients started on 5-ASA for the treatment of pediatric CD. The secondary aims were to evaluate the outcomes of those who continue 5-ASA to those who discontinue 5-ASA upon biologic escalation. Methods: We performed a single-center retrospective chart review of pediatric CD patients from 2010 to 2019 who were initially treated with 5-ASA. Demographics, medication and laboratory data, and clinical disease activity were collected. Results: Sixty-one patients were included in the study; the majority had inflammatory CD with ileocolonic involvement. Twenty-four patients were on a concomitant immunomodulator. The majority of patients (85.2%) required escalation to biologics. Thirty-two patients (61.5%) who escalated to biologic therapy continued on 5-ASA. Eighty percent of patients achieved clinical remission at 1 year, and there was no difference between those who continued 5-ASA at time of biologic initiation compared to those who did not continue the medication. Patients who discontinued 5-ASA had an average annual cost savings of $6741. Conclusion: 5-ASA is not a durable monotherapy for the treatment of pediatric CD. Patients who require escalation from 5-ASA to biologic therapy do not benefit from concomitant 5-ASA therapy. Further prospective studies are needed to confirm these findings.

Qing Hua Chang Yin alleviates chronic colitis of mice by protecting intestinal barrier function and improving colonic microflora.

Background: Qing Hua Chang Yin (QHCY) is a famous formula of traditional Chinese medicine (TCM) and has been proven to have protective effect on ulcerative colitis. However, its protective effect and potential therapeutic mechanisms in chronic colitis remain unclear. The purpose of this study is to explore the effects and underlying mechanisms of QHCY on dextran sulfate sodium (DSS)-induced chronic colitis mice model. Methods: The chronic colitis model was established by administration of 2% DSS for three consecutive cycles of 7 days with two intervals of 14 days for recovery by drinking water. The experiment lasted 49 days. The DSS + QHCY group received QHCY administration by oral gavage at doses of 1.6 g/kg/d, DSS + Mesalazine group was administrated Mesalazine by oral gavage at doses of 0.2 g/kg/d. The control and DSS group were given equal volume of distilled water. The body weight, stool consistency and blood in stool were monitored every 2 days. The disease activity index (DAI) was calculated. The colon length was measured after the mice were sacrificed. The histomorphology of colonic tissues was checked by the HE and PAS staining. Immunohistochemistry was performed to detect the expressions of pro-inflammatory cytokines (TNF-α, IL-1ß and IL-6), tight junction proteins (ZO-1, occludin) and Mucin2 (MUC2). 16S rRNA sequencing analysis was conducted to study the diversity and abundance of gut microbiota changes. Results: QHCY treatment not only significantly attenuated DSS-induced the weight loss, DAI score increase, colon shortening and histological damage in mice, but also decreased the expression of pro-inflammatory cytokines in colonic tissues and increased the expression of ZO-1, occludin, and MUC2. Furthermore, QHCY enhanced the diversity of gut microbes and regulated the structure and composition of intestinal microflora in mice with chronic colitis. Conclusion: QHCY has a therapeutic effect on a murine model of chronic colitis. It can effectively reduce the clinical and pathological manifestations of colitis and prevent alterations in the gut microbiota.

Double-Blind, Placebo-Controlled Study of Bezlotoxumab in Children Receiving Antibacterial Treatment for Clostridioides difficile Infection (MODIFY III).

BACKGROUND: Therapies to prevent recurrence of Clostridioides difficile infection (CDI) in pediatric patients are needed. Bezlotoxumab is a fully human monoclonal antibody approved for prevention of recurrent CDI in adults. We assessed the pharmacokinetics, safety, tolerability, and efficacy of bezlotoxumab in pediatric patients. METHODS: MODIFY III was a multicenter, double-blind, placebo-controlled study of bezlotoxumab in children (1 to <18 years) receiving antibacterial treatment for CDI. Participants were randomized 3:1 to receive a single infusion of bezlotoxumab (10 mg/kg) or placebo and were stratified by age at randomization (cohort 1: 12 to <18 years, cohort 2: 1 to <12 years). The primary objective was to characterize bezlotoxumab pharmacokinetics to support dose selection for pediatric patients; the primary endpoint was the area under the bezlotoxumab serum concentration-time curve (AUC0-inf). Safety, tolerability, and efficacy were monitored for 12 weeks post-infusion. RESULTS: A total of 148 participants were randomized and 143 were treated: 107 with bezlotoxumab and 36 with placebo (cohort 1 n = 60, cohort 2 n = 83; median age 9.0 years); 52.4% of participants were male and 80.4% were white. Geometric mean ratios (90% CI) for bezlotoxumab AUC0-inf were 1.06 (0.95, 1.18) and 0.82 (0.75, 0.89) h * µg/mL for cohorts 1 and 2, respectively. Bezlotoxumab 10 mg/kg was generally well-tolerated with an adverse event profile similar to placebo, including no treatment discontinuations due to adverse events. CDI recurrence was low and comparable for bezlotoxumab (11.2%) and placebo (14.7%). CONCLUSIONS: The results of this study support the bezlotoxumab dose of 10 mg/kg for pediatric patients. TRIAL REGISTRATION: NCT03182907 at ClinicalTrials.gov.

A Case of Cyclic Vomiting Syndrome-Induced Hypertension Causing Posterior Reversible Encephalopathy Syndrome.

Cyclic vomiting syndrome (CVS) is characterized by repeated episodes of vomiting in a stereotyped pattern and is a known cause of hypertension. Our patient is a 10-year-old female who presented with nonbilious, nonbloody vomiting, and constipation concerning for a flare of her known CVS. During the hospital course, she developed intermittent severe hypertensive episodes, leading to an acute episode of altered mental status and a tonic-clonic seizure. Magnetic resonance imaging confirmed diagnosis of posterior reversible encephalopathy syndrome (PRES) after eliminating other organic etiologies. This is one of the first documented cases of CVS-induced hypertension causing PRES.

Association of Anxiety and Gastrointestinal Comorbidities in Repeat Hospital Admissions in Pediatric Cyclic Vomiting Syndrome.

INTRODUCTION: Cyclic vomiting syndrome (CVS) is a functional gastrointestinal disorder with recurrent episodes of intense nausea and vomiting and thus may require frequent hospitalizations. There is paucity of data exploring the association of psychiatric and gastrointestinal comorbidities in repeat hospitalizations among pediatric patients with CVS. METHODS: We analyzed the Pediatric Health Information System database and included all patients up to 18 years of age with a diagnosis of CVS between 2016 and 2020. We excluded patients with chronic conditions, which mimic CVS. The primary outcome variable was 90-day admission rate, which was defined as a visit to emergency department or admission to observation/inpatient unit with a primary diagnosis of CVS within 90 days after an index CVS hospitalization. RESULTS: We evaluated a total of 2,604 hospitalizations represented by 1,370 unique individuals. The overall 90-day admission rate was 28.5%, which steadily decreased from 35.7% in 2016 to 23% in 2019 ( P < 0.001). Patients in the repeat hospitalization cohort were slightly older and more often men. Patients with repeat admissions had an increased proportion of anxiety and other gastrointestinal disorders. Multivariable logistic regression showed that anxiety, gastroesophageal reflux disease, functional dyspepsia, and abdominal migraine were associated with increased odds of repeat admissions. DISCUSSION: Ninety-day admission rates in pediatric CVS are decreasing overall, although still contributing to significant healthcare expenditure. Anxiety and gastrointestinal comorbidities were associated with increased risk of repeat admissions. Further prospective studies are needed to better understand the complex interactions of these comorbidities and their management affecting the natural course of CVS.

Cytomegalovirus Infection Is Associated With Adverse Outcomes Among Hospitalized Pediatric Patients With Inflammatory Bowel Disease.

Background: Adults with inflammatory bowel disease (IBD) are at increased risk of developing cytomegalovirus (CMV) colitis, which is associated with adverse outcomes. Similar studies in pediatric IBD patients are lacking. Methods: We analyzed non-overlapping years of National Inpatient Sample (NIS) and Kids Inpatient Database (KID) between 2003 and 2016. We included all patients < 21 years with a diagnosis of Crohn's disease (CD) or ulcerative colitis (UC). Patients with coexisting CMV infection during that admission were compared with patients without CMV infection for outcome measures such as in-hospital mortality, disease severity, and healthcare resource utilization. Results: We analyzed a total of 254,839 IBD-related hospitalizations. The overall prevalence rate of CMV infection was 0.3% with an overall increasing prevalence trend, P < 0.001. Approximately two-thirds of patients with CMV infection had UC, which was associated with almost 3.6 times increased risk of CMV infection (confidence interval (CI): 3.11 to 4.31, P < 0.001). IBD patients with CMV had more comorbid conditions. CMV infection was significantly associated with increased odds of in-hospital mortality (odds ratio (OR): 3.58; CI: 1.85 to 6.93, P < 0.001) and severe IBD (OR: 3.31; CI: 2.54 to 4.32, P < 0.001). CMV-related IBD hospitalizations had increased length of stay by 9 days while incurring almost $65,000 higher hospitalization charges, P < 0.001. Conclusions: The prevalence of CMV infection is increasing in pediatric IBD patients. CMV infections significantly corelated with increased risk of mortality and severity of IBD leading to prolonged hospital stay and higher hospitalization charges. Further prospective studies are needed to better understand the factors leading to this increasing CMV infection.

Comparison of Short-Term Outcomes for Standard Versus Nonstandard Induction Dosing of Infliximab for Pediatric Inflammatory Bowel Disease.

OBJECTIVE: Recent studies have emphasized the early use of infliximab (IFX) in pediatric patients with inflammatory bowel disease. Standard dosing of 5 mg/kg/dose may not be sufficient to achieve optimal clinical outcomes. The aim of our study was to compare short-term outcomes with standard dosing of IFX to higher, nonstandard dosing of IFX for induction therapy. METHODS: Retrospective study of 162 pediatric patients receiving either standard (5-6 mg/kg, n = 90) or nonstandard (>6 mg/kg, n = 72) dosing of IFX during induction was performed. Patient demographics, clinical outcomes, and laboratory data were collected. Need for dose escalation during the first 6 months, combination therapy with immunomodulators, and steroid-free progression were investigated. RESULTS: Clinical remission rates between the 2 groups were significantly different, with patients receiving nonstandard dosing demonstrating higher rates (58% vs 78%; p = 0.012). Use of combination therapy with immunomodulators was significantly different between standard and nonstandard groups (80% vs 48%; p < 0.001). Numeric trend in need for IFX dose escalation in the first 6 months was seen between standard and nonstandard groups (54% vs 39%, respectively; p = 0.087). Post-induction IFX trough concentrations, rates of antibody development, drug discontinuation, and infusion reaction were similar. CONCLUSIONS: Nonstandard induction dosing of IFX was associated with higher rates of clinical remission, despite similar rates of serum IFX trough concentrations. There was a numeric trend towards the standard group requiring dose escalation within the first 6 months of therapy. Patients given nonstandard dosing may achieve superior clinical outcomes compared with those on standard dosing.

Pediatric endoscopy across multiple clinical settings: Efficiency and adverse events.

BACKGROUND: Endoscopic procedures are becoming increasingly important for the diagnosis and treatment of gastrointestinal disorders during childhood, and have evolved from a more infrequent inpatient procedure in the operating room to a routine outpatient procedure conducted in multiple care settings. Demand for these procedures is rapidly increasing and thus there is a need to perform them in an efficient manner. However, there are little data comparing the efficiency of pediatric endoscopic procedures in diverse clinical environments. We hypothesized that there are significant differences in efficiency between settings. AIM: To compare the efficiency and examine adverse effects of pediatric endoscopic procedures across three clinical settings. METHODS: A retrospective chart review was conducted on 1623 cases of esophagogastroduodenoscopy (EGD) or combined EGD and colonoscopy performed between January 1, 2014 and May 31, 2018 by 6 experienced pediatric gastroenterologists in three different clinical settings, including a tertiary care hospital operating room, community hospital operating room, and free-standing pediatric ambulatory endoscopy center at a community hospital. The following strict guidelines were used to schedule patients at all three locations: age greater than 6 mo; American Society of Anesthesiologists class 1 or 2; normal craniofacial anatomy; no anticipated therapeutic intervention (e.g., foreign body retrieval, stricture dilation); and, no planned or anticipated hospitalization post-procedure. Data on demographics, times, admission rates, and adverse events were collected. Endoscopist time (elapsed time from the endoscopist entering the operating room or endoscopy suite to the next patient entering) and patient time (elapsed time from patient registration to that patient exiting the operating room or endoscopy suite) were calculated to assess efficiency. RESULTS: In total, 58% of the cases were performed in the tertiary care operating room. The median age of patients was 12 years and the male-to-female ratio was nearly equal across all locations. Endoscopist time at the tertiary care operating room was 12 min longer compared to the community operating room (63.3 ± 21.5 min vs 51.4 ± 18.9 min, P < 0.001) and 7 min longer compared to the endoscopy center (vs 56.6 ± 19.3 min, P < 0.001). Patient time at the tertiary care operating room was 11 min longer compared to the community operating room (133.2 ± 39.9 min vs 122.3 ± 39.5 min, P < 0.001) and 9 min longer compared to the endoscopy center (vs 124.9 ± 37.9 min; P < 0.001). When comparing endoscopist and patient times for EGD and EGD/colonoscopies among the three locations, endoscopist, and patient times were again shorter in the community hospital and endoscopy center compared to the tertiary care operating room. Adverse events from procedures occurred in 0.1% (n = 2) of cases performed in the tertiary care operating room, with 2.2% (n = 35) of cases from all locations having required an unplanned admission after the endoscopy for management of a primary GI disorder. CONCLUSION: Pediatric endoscopic procedures can be conducted more efficiently in select patients in a community operating room and endoscopy center compared to a tertiary care operating room.

Epidemiology of Eosinophilic Esophagitis in Patients with Cystic Fibrosis: A Population-Based 5-Year Study.

Purpose: The prevalence of eosinophilic esophagitis (EoE) has been on the rise since it was first described in the 1990s. Several diseases and exogenous factors have been associated with EoE. Our aim was to investigate the epidemiology of EoE in cystic fibrosis (CF) patients. Methods: We identified individuals with CF from September 2014 to September 2019 within a database (IBM Explorys Solutions, Inc.). The prevalence of EoE in patients with CF was compared to the general population. Results: The database included 36,111,860 patients during the 5-year study period: 12,950 with CF (0.036%) and 28,090 with EoE (0.078%). EoE prevalence was higher in CF patients than the general population (46 in 10,000 vs. 7.8 in 10,000, p<0.001). Patients with CF and EoE were more likely to be male (50% vs. 33.5%, p<0.008), children (33.3% vs. 16.5%, p<0.001), and non-Hispanic (100% vs. 88.7%, p<0.001) than CF patients without EoE. CF with EoE patients were more likely to be children than EoE only (33.3% vs. 10.5%, p<0.001). Allergic conditions were generally more prevalent in CF with EoE than CF only (83.3% vs. 68.3%, p=0.01) and EoE only (83.3% vs. 69.3%, p=0.014). Conclusion: EoE is nearly 6-times more prevalent in CF patients. Those patients had higher incidence of other atopic conditions. EoE must be considered in the differential diagnosis of patients with CF presenting with dysphagia, refractory gastroesophageal reflux, vomiting, and other esophagus-related symptoms.

Cystic fibrosis-related liver disease is an independent risk factor for mortality and increased health care resource utilization in hospitalized pediatric patients with cystic fibrosis.

BACKGROUND: Cystic fibrosis-related liver disease (CFLD) is more prevalent in recent decades due to the increasing life expectancy of patients with cystic fibrosis (CF). There is paucity of population-level data on the impact of CFLD on hospital outcomes. METHODS: We interrogated nonoverlapping years (2003-2016) of the National Inpatient Sample and Kids' Inpatient Database to include all hospitalized patients <21 years of age with a primary diagnosis of CF within the United States. A concomitant diagnosis of cirrhosis, liver fibrosis, chronic liver disease, portal hypertension, hepatomegaly, splenomegaly, hypersplenism, and liver transplant status was considered as surrogates for the diagnosis of CFLD and was compared with CF-related hospitalizations without these diagnoses (controls) for demographics, comorbid conditions, in-hospital mortality, length-of-stay, and hospital charges. RESULTS: We evaluated 94,374 CF-related hospitalizations. The prevalence of CFLD was 5.8%. The prevalence increased from 3.1% (2003) to a peak of 7.3% (2014) with an overall increasing trend, p < 0.001. Hospitalizations with CFLD had an increased prevalence of significant comorbidities: respiratory failure,lung transplant, pulmonary hypertension, diabetes mellitus, malnutrition, Clostridioides difficile infection, cholelithiasis, anemia, and need for parenteral nutrition, p < 0.001. Multivariate regression models showed CFLD as independently associated with 2.1 (95% confidence interval [CI]: 1.5 to 2.8) times increased risk of inpatient mortality, contributed to 1.1 (95% CI: 0.89 to 1.37) additional days of hospitalization, and incurring $14,852 (95% CI: 12,204 to 17,501) excess hospital charges, p < 0.001. CONCLUSION: CFLD is associated with multiple comorbidities and is independently associated with increased risk of mortality and increased health care resource utilization in pediatric CF-related hospitalizations.

Ribosome assembly factor PNO1 is associated with progression and promotes tumorigenesis in triple­negative breast cancer.

The aim of the present study was to investigate the expression of ribosome assembly factor partner of NOB1 homolog (PNO1) and its association with the progression of breast cancer (BC) in patients, as well as its biological function and underlying mechanism of action in BC cells. Bioinformatics and immunohistochemical analyses revealed that PNO1 expression was significantly increased in BC tissues and its high mRNA expression was associated with shorter overall survival (OS) and relapse­free survival (RFS) of patients with BC, as well as multiple clinical characteristics (including advanced stage of NPI and SBR, etc.) of patients with BC. Biological functional studies revealed that transduction of lentivirus encoding sh­PNO1 significantly downregulated PNO1 expression, reduced cell confluency and the number of BC cells in vitro and inhibited tumor growth in vivo. Moreover, PNO1 knockdown decreased the cell viability and arrested cell cycle progression at the G2/M phase, as well as downregulated cyclin B1 (CCNB1) and cyclin­dependent kinase 1 (CDK1) protein expression in BC cells. Correlation analysis demonstrated that PNO1 expression was positively correlated with both CDK1 and CCNB1 expression in BC samples. Collectively, PNO1 was upregulated in BC and associated with BC patient survival, and PNO1 knockdown suppressed tumor growth in vitro and in vivo. In addition, positive regulation of CCNB1 and CDK1 may be one of the underlying mechanisms.

Differences in Clinical Presentation of Eosinophilic Esophagitis in Pediatric Patients With Ulcerative Colitis and Crohn Disease.

SIGNIFICANCE: Eosinophilic esophagitis (EoE) is an inflammatory condition characterized by T helper-2 (T H 2) cytokines. Ulcerative colitis (UC) and Crohn disease (CD) are inflammatory conditions with different clinical presentations and immune profiles. UC is associated with T H 2 cytokines and CD with T H 1 cytokines. We investigated potential differences in the association of EoE with UC and CD because of these different immune profiles. METHODS: We utilized ICD-9 and ICD-10 codes to find patients with inflammatory bowel disease (IBD) and EoE. We defined EoE as any esophageal biopsy with >15 eosinophils. We collected demographic, clinical, laboratory, endoscopic, and histological data. RESULTS: Thirty patients had both EoE and IBD. 14.9% of UC patients had EoE and 5.7% of CD patients had EoE. 64.7% of UC patients presented with UC and EoE at the same time, whereas 76.9% of CD patients presented with EoE at follow up. Ten of 13 CD patients were on anti-tumor necrosis factor (TNF) at EoE diagnosis. No UC patients were on anti-TNF at EoE diagnosis. Eighty-three percent of CD patients had mild disease or were in remission, whereas 50% of UC patients had moderate to severe disease at the time of EoE diagnosis. CONCLUSION: A higher percentage of UC than CD patients had EoE. EoE was more likely to be present at the initial diagnosis of UC than CD. EoE was more likely after diagnosis and treatment of CD with anti-TNF, when CD activity was mild or in remission. The difference in presentation suggests that anti-TNF or it's impact on inflammation may differentially impact the association of EoE with CD and UC.

Acute Pancreatitis Is Associated with Increased Risk of In-Hospital Mortality and Health Care Utilization Among Pediatric Patients with Hematopoietic Stem Cell Transplantation.

OBJECTIVE: To analyze the impact of acute pancreatitis on mortality and hospital outcomes among the pediatric population following hematopoietic stem cell transplantation (HSCT). STUDY DESIGN: We analyzed nationally representative, nonoverlapping years of the National Inpatient Sample and Kids Inpatient Database between 2003 and 2016, including all pediatric patients who had HSCT. Patients were divided into those with and without a diagnosis of acute pancreatitis and compared for demographics, clinical characteristics, comorbid conditions related to both HSCT and acute pancreatitis, and outcome measures such as in-hospital mortality and health care resource use (length of hospital stay and total hospitalization charges). RESULTS: We analyzed a total of 128 772 hospitalizations of children and adolescents with HSCT. The overall incidence rate of acute pancreatitis was approximately 1%, with an overall increasing trend between 2003 and 2016, P < .001. The overall mortality rate was significantly greater among patients with acute pancreatitis (14.9% vs 3.6%, P < .001). Multivariate regression analysis showed that acute pancreatitis was independently associated with 3.4 times (95% CI 2.86-4.02, P < .001) increased risk of in-hospital mortality. Patients with acute pancreatitis who underwent HSCT had a greater incidence of end-organ damage and thrombotic events. Pediatric acute pancreatitis was associated with 24.3 additional days of hospitalization (95% CI 22.9-25.7, P < .001) and incurred additional $213 496 in hospitalization charges (95% CI 193 768-233 063, P < .001). CONCLUSIONS: Pediatric recipients of HSCT who develop acute pancreatitis have adverse outcomes with increased in-hospital mortality, end-organ damage, prolonged hospital stay, and greater hospitalization charges.

Role of Traditional Chinese Herbal Medicines in Functional Gastrointestinal and Motility Disorders.

PURPOSE OF REVIEW: Traditional Chinese medicine (TCM) has been in use for thousands of years in Asian countries and is rapidly gaining popularity in the Western world. Among different forms of TCM, the traditional Chinese herbal therapy and acupuncture are the most popular modalities. Here, we review the fundamentals of TCMs for clinicians practicing in the West and will also detail the evidence-based utility of Chinese herbal medicine in the management of functional gastrointestinal disorders (FGIDs). RECENT FINDINGS: In the recent decades, the popularity and usage of traditional Chinese herbal medicine in FGIDs is increasing in the West. TCMs are commonly utilized by many patients with FGIDs as the conventional therapies do have limitations such as cost, inadequate symptom control and adverse effects. The unfamiliarity of TCM philosophy among clinicians in the West, and shortage of traditional Chinese herbalists remain. The philosophy of TCM is complex and entirely different from the Western medical concepts and is difficult to understand for a clinician trained in the West. Further traditional Chinese herbal therapies are often viewed skeptically by the clinicians in the West for various reasons such as lack of scientific rigor, inconsistencies in the constituents of herbal products, and also concerns due to adverse herb effects. Future clinical trials in FGIDs should focus on herb product quality, herb-drug interactions, and standardized criteria for diagnosis and management outcomes.

Upregulation of SNTB1 correlates with poor prognosis and promotes cell growth by negative regulating PKN2 in colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) is one of the most highly malignant tumors and has a complicated pathogenesis. A preliminary study identified syntrophin beta 1 (SNTB1) as a potential oncogene in CRC. However, the clinical significance, biological function, and underlying mechanisms of SNTB1 in CRC remain largely unknown. Thus, the present study aimed to investigate the role of SNTB1 in CRC. METHODS: The expression profile of SNTB1 in CRC samples was evaluated by database analysis, cDNA array, tissue microarray, quantitative real-time PCR (qPCR), and immunohistochemistry. SNTB1 expression in human CRC cells was silenced using short hairpin RNAs (shRNA)/small interfering RNAs (siRNA) and its mRNA and protein levels were assessed by qPCR and/or western blotting. Cell viability, survival, cell cycle, and apoptosis were determined by the CCK-8 assay, colony formation, and flow cytometry assays, respectively. A xenograft nude mouse model of CRC was established to validate the roles of SNTB1 in vivo. Immunohistochemistry and TUNEL staining were used to determine the expression of SNTB1, PCNA, and cell apoptosis in tissue samples. Isobaric tag for relative and absolute quantification (iTRAQ) was used to analyze the differentially expressed proteins after knockdown of SNTB1 in CRC cells. Silence of protein kinase N2 (PKN2) using si-PNK2 was performed for rescue experiments. RESULTS: SNTB1 expression was increased in CRC tissues compared with adjacent noncancerous tissues and the increased SNTB1 expression was associated with shorter overall survival of CRC patients. Silencing of SNTB1 suppressed cell viability and survival, induced cell cycle arrest and apoptosis in vitro, and inhibited the growth of CRC cells in vivo. Further elucidation of the regulation of STNB1 on CRC growth by iTRAQ analysis identified 210 up-regulated and 55 down-regulated proteins in CRC cells after SNTB knockdown. A PPI network analysis identified PKN2 as a hub protein and was up-regulated in CRC cells after SNTB1 knockdown. Western-blot analysis further confirmed that SNTB1 knockdown significantly up-regulated PKN2 protein expression in CRC cells and decreased the phosphorylation of both ERK1/2 and AKT. Moreover, rescue experiments indicated that PKN2 knockdown significantly rescued SNTB1 knockdown-mediated decrease in cell viability, survival, and increase of cell cycle arrest at G0/G1 phase and apoptosis of CRC cells. CONCLUSIONS: These findings indicate that SNTB1 is overexpressed in CRC. Elevated SNTB1 levels are correlated with shorter patient survival. Importantly, SNTB1 promotes tumor growth and progression of CRC, possibly by reducing the expression of PKN2 and activating the ERK and AKT signaling pathway. Our study highlights the potential of SNTB1 as a new prognostic factor and therapeutic target for CRC.

Targeting NUFIP1 Suppresses Growth and Induces Senescence of Colorectal Cancer Cells.

NUFIP1 is an RNA-binding protein that interacts with fragile X mental retardation protein (FMRP) in the messenger ribonucleoprotein particle (mRNP). We previously showed that NUFIP1 was upregulated in colorectal cancer (CRC), but how the protein may contribute to the disease and patient prognosis is unknown. Here we combine database analysis, microarray, quantitative PCR, and immunohistochemistry of patients' samples to confirm our previous findings on NUFIP1 overexpression in CRC, and to reveal that increased expression of NUFIP1 in CRC tissues correlated with worse overall, recurrence-free, event-free and disease-free survival in patients, as well as with more advanced CRC clinicopathological stage. Loss of function analysis demonstrated that NUFIP1 knockdown suppressed cell growth in vitro and in vivo, inhibited cell viability and survival, and induced cell cycle arrest and apoptosis in vitro, as well as up-regulated Bax and down-regulated Bcl-2 protein expression. In addition, as a natural anticancer triterpene from various fruits and vegetables, ursolic acid (UA) treatment suppressed cell proliferation, down-regulated NUFIP1 protein expression, and further enhanced the effects of NUFIP1 knockdown in CRC cells in vitro. NUFIP1 knockdown up-regulated the expression of 136 proteins, down-regulated the expression of 41 proteins, and enriched multiple signaling pathways including the senescence-associated heterochromatin foci (SAHF) pathway. Furthermore, NUFIP1 knockdown enhanced the expression of senescence-associated-ß-galactosidase (SA-ß-gal), the SAHF markers HP1γ and trimethylation (H3k9me3), and the senescence-related protein HMGA2, as well as both p53 and its downstream p21 protein expression. Our findings suggest that NUFIP1 is overexpressed in CRC and correlates with disease progression and poor patient survival. NUFIP1 may exert oncogenic effects partly by altering senescence. UA may show potential to treat CRC by down-regulating NUFIP1.

Impact of Altered Gut Microbiota and Its Metabolites in Cystic Fibrosis.

Cystic fibrosis (CF) is the most common lethal, multisystemic genetic disorder in Caucasians. Mutations in the gene encoding the cystic fibrosis transmembrane regulator (CFTR) protein are responsible for impairment of epithelial anionic transport, leading to impaired fluid regulation and pH imbalance across multiple organs. Gastrointestinal (GI) manifestations in CF may begin in utero and continue throughout the life, resulting in a chronic state of an altered intestinal milieu. Inherent dysfunction of CFTR leads to dysbiosis of the gut. This state of dysbiosis is further perpetuated by acquired factors such as use of antibiotics for recurrent pulmonary exacerbations. Since the gastrointestinal microbiome and their metabolites play a vital role in nutrition, metabolic, inflammatory, and immune functions, the gut dysbiosis will in turn impact various manifestations of CF-both GI and extra-GI. This review focuses on the consequences of gut dysbiosis and its metabolic implications on CF disease and possible ways to restore homeostasis.

Effects of Qing Hua Chang Yin on lipopolysaccharide­induced intestinal epithelial tight junction injury in Caco­2 cells.

Disruption of the intestinal mucosal barrier integrity is a pathogenic process in inflammatory bowel disease (IBD) development, and is therefore considered a drug discovery target for IBD. The well­known traditional Chinese formulation Qing Hua Chang Yin (QHCY) has been suggested as a potential therapeutic agent for the treatment of ulcerative colitis. However, the possible underlying molecular mechanisms regarding its therapeutic effect remain unclear. Consequently, the present study investigated the effects of QHCY on lipopolysaccharide (LPS)­induced loss of intestinal epithelial barrier integrity in vitro using the Caco­2 cell model of intestinal epithelium. QHCY reversed the LPS­induced decrease in transepithelial electrical resistance and significantly alleviated the increased fluorescently­labeled dextran 4 flux caused by LPS. Moreover, QHCY upregulated the mRNA and protein expression levels of occludin, zona occludens­1 and claudin­1 in LPS­exposed Caco­2 cells. In conclusion, QHCY was able to protect intestinal epithelial barrier integrity following an inflammatory insult; the protective effects of QHCY may be mediated by modulation of the expression of tight junction proteins.