Effects of Clip Anchoring on Preventing Migration of Fully Covered Self-Expandable Metal Stent in Patients Undergoing Endoscopic Retrograde Cholangiopancreatography: A Multicenter, Randomized Controlled Study.

INTRODUCTION: Fully covered self-expandable metal stents (FCSEMSs) are commonly placed in patients with biliary stricture during endoscopic retrograde cholangiopancreatography (ERCP). However, up to 40% of migration has been reported, resulting in treatment failure or the requirement for further intervention. Here, we aimed to investigate the effects of metal clip anchoring on preventing the migration of FCSEMS. METHODS: Consecutive patients requiring placement of FCSEMS were included in this multicenter randomized trial. The enrolled patients were randomly assigned in a 1:1 ratio to receive clip anchoring (clip group) or not (control group). The primary outcome was the migration rate at 6 months after stent insertion. The secondary outcomes were the rates of proximal and distal migration and stent-related adverse events. The analysis followed the intention-to-treat principle. RESULTS: From February 2020 to November 2022, 180 patients with biliary stricture were enrolled, with 90 in each group. The baseline characteristics were comparable between the 2 groups. The overall rate of stent migration at 6 months was significantly lower in the clip group compared with the control group (16.7% vs 30.0%, P = 0.030). The proximal and distal migration rates were similar in the 2 groups (2.2% vs 5.6%, P = 0.205; 14.4% vs 22.2%, P = 0.070). Notably, none of the patients (0/8) who received 2 or more clips experienced stent migration. There were no significant differences in stent-related adverse events between the 2 groups. DISCUSSION: Our data suggest that clip-assisted anchoring is an effective and safe method for preventing migration of FCSEMS without increasing the adverse events.

SfREPAT38, a pathogen response gene (REPAT), is involved in immune response of Spodoptera frugiperda larvae through mediating Toll signalling pathway.

REPAT (response to pathogen) is an immune-associated gene family that plays important roles in insect immune response to pathogens. Although nine REPAT genes have been identified in Spodoptera frugiperda (Lepidoptera: Noctuidae) currently, their functions and mechanisms in the immune response to pathogens still remain unclear. Therefore, SfREPAT38, a pathogen response gene (REPAT) of S. frugiperda, was characterised and its function was analysed. The results showed that SfREPAT38 contains a signal peptide and a transcription activator MBF2 (multi-protein bridging factor 2) domain. Quantitative real-time polymerase chain reaction analysis showed that SfREPAT38 was highly expressed in the sixth-instar larvae (L6) and was the highest in expression in the midgut of L6. We found that the expression of SfREPAT38 could be activated by challenge with four microbial pathogens (Bacillus thuringiensis, Metarhizium anisopliae, Spodoptera exigua nuclearpolyhedrosis and Escherichia coli), except 12 h after E. coli infection. Furthermore, the SfREPAT38 expression levels significantly decreased at 24, 48 and 72 h after SfREPAT38 dsRNA injection or feeding. Feeding with SfREPAT38 dsRNA significantly decreased the weight gain of S. frugiperda, and continuous feeding led to the death of S. frugiperda larvae from the fourth day. Moreover, SfREPAT38 dsRNA injection resulted in a significant decrease of weight gain on the fifth day. Silencing SfREPAT38 gene down-regulated the expression levels of immune genes belonging to the Toll pathway, including SPZ, Myd88, DIF, Cactus, Pell and Toll18W. After treatment with SfREPAT38 dsRNA, S. frugiperda became extremely sensitive to the B. thuringiensis infection, and the survival rate dramatically increased, with 100% mortality by the eighth day. The weight of S. frugiperda larvae was also significantly lower than that of the control groups from the second day onwards. In addition, the genes involved in the Toll signalling pathway and a few antibacterial peptide related genes were down-regulated after treatment. These results showed that SfREPAT38 is involved in the immune response of S. frugiperda larvae through mediating Toll signalling pathway.

The role of amino acid metabolism alterations in acute ischemic stroke: From mechanism to application.

Acute ischemic stroke (AIS) is the most prevalent type of stroke, and due to its high incidence, disability rate, and mortality rate, it imposes a significant burden on the health care system. Amino acids constitute one of the most crucial metabolic products within the human body, and alterations in their metabolic pathways have been identified in the microenvironment of AIS, thereby influencing the pathogenesis, severity, and prognosis of AIS. The amino acid metabolism characteristics in AIS are complex. On one hand, the dynamic progression of AIS continuously reshapes the amino acid metabolism pattern. Conversely, changes in the amino acid metabolism pattern also exert a double-edged effect on AIS. This interaction is bidirectional, dynamic, heterogeneous, and dose-specific. Therefore, the distinctive metabolic reprogramming features surrounding amino acids during the AIS process are systematically summarized in this paper, aiming to provide potential investigative strategies for the early diagnosis, treatment approaches, and prognostic enhancement of AIS.

Structural insights into the unusual core photocomplex from a triply extremophilic purple bacterium, Halorhodospira halochloris.

Halorhodospira (Hlr.) halochloris is a triply extremophilic phototrophic purple sulfur bacterium, as it is thermophilic, alkaliphilic, and extremely halophilic. The light-harvesting-reaction center (LH1-RC) core complex of this bacterium displays an LH1-Qy transition at 1,016 nm, which is the lowest-energy wavelength absorption among all known phototrophs. Here we report the cryo-EM structure of the LH1-RC at 2.42 Å resolution. The LH1 complex forms a tricyclic ring structure composed of 16 αßγ-polypeptides and one αß-heterodimer around the RC. From the cryo-EM density map, two previously unrecognized integral membrane proteins, referred to as protein G and protein Q, were identified. Both of these proteins are single transmembrane-spanning helices located between the LH1 ring and the RC L-subunit and are absent from the LH1-RC complexes of all other purple bacteria of which the structures have been determined so far. Besides bacteriochlorophyll b molecules (B1020) located on the periplasmic side of the Hlr. halochloris membrane, there are also two arrays of bacteriochlorophyll b molecules (B800 and B820) located on the cytoplasmic side. Only a single copy of a carotenoid (lycopene) was resolved in the Hlr. halochloris LH1-α3ß3 and this was positioned within the complex. The potential quinone channel should be the space between the LH1-α3ß3 that accommodates the single lycopene but does not contain a γ-polypeptide, B800 and B820. Our results provide a structural explanation for the unusual Qy red shift and carotenoid absorption in the Hlr. halochloris spectrum and reveal new insights into photosynthetic mechanisms employed by a species that thrives under the harshest conditions of any phototrophic microorganism known.

The Protective Role of Non-Photochemical Quenching in PSII Photo-Susceptibility: A Case Study in the Field.

Non-photochemical quenching (NPQ) has been regarded as a safety valve to dissipate excess absorbed light energy not used for photochemistry. However, there exists no general consensus on the photoprotective role of NPQ. In the present study, we quantified the Photosystem II (PSII) photo-susceptibilities (mpi) in the presence of lincomycin, under red light given to five shade-acclimated tree species grown in the field. Photosynthetic energy partitioning theory was applied to investigate the relationships between mpi and each of the regulatory light-induced NPQ [Y(NPQ)], the quantum yield of the constitutive nonregulatory NPQ [Y(NO)] and the PSII photochemical yield in the light-adapted state [Y(PSII)] under different red irradiances. It was found that in the low to moderate irradiance range (50-800 µmol m-2 s-1) when the fraction of open reaction centers (qP) exceeded 0.4, mpi exhibited no association with Y(NPQ), Y(NO) and Y(PSII) across species. However, when qP < 0.4 (1,500 µmol m-2 s-1), there existed positive relationships between mpi and Y(NPQ) or Y(NO) but a negative relationship between mpi and Y(PSII). It is postulated that both Y(NPQ) and Y(NO) contain protective and damage components and that using only Y(NPQ) or Y(NO) metrics to identify the photo-susceptibility of a species is a risk. It seems that qP regulates the balance of the two components for each of Y(NPQ) and Y(NO). Under strong irradiance, when both protective Y(NPQ) and Y(NO) are saturated/depressed, the forward electron flow [i.e. Y(PSII)] acts as the last defense to resist photoinhibition.

Transcutaneous Auricular Vagal Nerve Stimulation Is Effective for the Treatment of Functional Dyspepsia: A Multicenter, Randomized Controlled Study.

INTRODUCTION: Vagal nerve stimulation (VNS) can be used to modulate gastrointestinal motility, inflammation, and nociception. However, it remains unclear whether VNS is effective in adult patients with functional dyspepsia (FD). We investigated the effectiveness of transcutaneous auricular VNS (taVNS) in patients with FD. METHODS: Consecutive patients with FD meeting Rome IV criteria with modified FD Symptom Diary score ≥10 were enrolled. Patients were randomly allocated to 10-Hz taVNS (V10 group), 25-Hz taVNS (V25 group), or sham group, with 30 minutes of treatment twice a day for 4 weeks. The primary outcome was the response rate at week 4, defined as the proportion of patients whose modified FD Symptom Diary score was reduced ≥5 when compared with the baseline. Secondary outcomes included adequate relief rate and adverse events. RESULTS: A total of 300 patients were randomized to V10 (n = 101), V25 (n = 99), and sham groups (n = 100). After 4 weeks of treatment, V10 and V25 groups had a higher response rate (81.2% vs 75.9% vs 47%, both P < 0.001) and adequate relief rate (85.1% vs 80.8% vs 67%, both P < 0.05) compared with the sham group. There was no significant difference between V10 and V25 in response rate and adequate relief rate (both P > 0.05). The efficacy of taVNS (both 10 and 25 Hz) lasted at week 8 and week 12 during follow-up period. Adverse events were all mild and comparable among the 3 groups (1%-3%). DISCUSSION: Our study firstly showed that 4-week taVNS (both 10 and 25 Hz) was effective and safe for the treatment of adult FD ( clinicaltrials.gov number: NCT04668534).

Exposed anthocyanic leaves of Prunus cerasifera are special shade leaves with high resistance to blue light but low resistance to red light against photoinhibition of photosynthesis.

BACKGROUND AND AIMS: The photoprotective role of foliar anthocyanins has long been ambiguous: exacerbating, being indifferent to or ameliorating the photoinhibition of photosynthesis. The photoinhibitory light spectrum and failure to separate photo-resistance from repair, as well as the different methods used to quantify the photo-susceptibility of the photosystems, could lead to such a discrepancy. METHODS: We selected two congeneric deciduous shrubs, Prunus cerasifera with anthocyanic leaves and Prunus triloba with green leaves, grown under identical growth conditions in an open field. The photo-susceptibilities of photosystem II (PSII) and photosystem I (PSI) to red light and blue light, in the presence of lincomycin (to block the repair), of exposed leaves were quantified by a non-intrusive P700+ signal from PSI. Leaf absorption, pigments, gas exchange and Chl a fluorescence were also measured. KEY RESULTS: The content of anthocyanins in red leaves (P. cerasifera) was >13 times greater than that in green leaves (P. triloba). With no difference in maximum quantum efficiency of PSII photochemistry (Fv/Fm) and apparent CO2 quantum yield (AQY) in red light, anthocyanic leaves (P. cerasifera) showed some shade-acclimated suites, including lower Chl a/b ratio, lower photosynthesis rate, lower stomatal conductance and lower PSII/PSI ratio (on an arbitrary scale), compared with green leaves (P. triloba). In the absence of repair of PSII, anthocyanic leaves (P. cerasifera) showed a rate coefficient of PSII photoinactivation (ki) that was 1.8 times higher than that of green leaves (P. triloba) under red light, but significantly lower (-18 %) under blue light. PSI of both types of leaves was not photoinactivated under blue or red light. CONCLUSIONS: In the absence of repair, anthocyanic leaves exhibited an exacerbation of PSII photoinactivation under red light and a mitigation under blue light, which can partially reconcile the existing controversy in terms of the photoprotection by anthocyanins. Overall, the results demonstrate that appropriate methodology applied to test the photoprotection hypothesis of anthocyanins is critical.

GhMYB18 confers Aphis gossypii Glover resistance through regulating the synthesis of salicylic acid and flavonoids in cotton plants.

KEY MESSAGE: R2R3 MYB transcription factor GhMYB18 is involved in the defense response to cotton aphid by participating in the synthesis of salicylic acid and flavonoids. R2R3 MYB transcription factors (TFs) play crucial roles in plant growth and development as well as response to abiotic and biotic stresses. However, the mechanism of R2R3 MYB TFs in cotton response to aphid infestation remains largely unknown. Here, an R2R3 MYB transcription factor GhMYB18 was identified as a gene up-regulated from upland cotton (Gossypium hirsutum L.) under cotton aphid (Aphis gossypii Glover) infestation. GhMYB18, which has transcription activity, was localized mainly to nucleus and cell membranes. Transient overexpression of GhMYB18 in cotton activates salicylic acid (SA) and phenylpropane signaling pathways and promoted the synthesis of salicylic acid and flavonoids, which leads to enhancing the tolerance to cotton aphid feeding. In contrast, silencing of GhMYB18 increased the susceptibility of G. hirsutum to aphid. Additionally, GhMYB18 significantly promoted the activities of defense-related enzymes including catalase (CAT), peroxidase (POD), polyphenol oxidase (PPO) and phenylalanine ammonia-lyase (PAL). These results collectively suggest that GhMYB18 is involved in cotton defense response to cotton aphid attacks through regulating the synthesis of salicylic acid and flavonoids.

Endoscopic Papillary Large Balloon Dilation Reduces Further Recurrence in Patients With Recurrent Common Bile Duct Stones: A Randomized Controlled Trial.

INTRODUCTION: Up to 60% of patients with common bile duct stone (CBDS) recurrence suffer from further recurrence after endoscopic retrograde cholangiopancreatography (ERCP). There are no effective methods to prevent recurrence in most patients. In this study, we aimed to assess the short-term and long-term efficacies of endoscopic papillary large balloon dilation (EPLBD) for the management of recurrent CBDS in a randomized controlled trial. METHODS: Consecutive patients with recurrent CBDS were eligible and randomly assigned in a 1:1 ratio to the EPLBD group or the control group. The primary outcome was the CBDS recurrence rate within 2 years after ERCP. The analysis followed the intention-to-treat principle. RESULTS: From 2014 to 2021, 180 patients with recurrent CBDS were included, with 90 in each group. All patients underwent complete CBDS clearance by 1 or several sessions of ERCP. The rate of complete clearance in 1 session was significantly higher with EPLBD treatment (95.6% vs 85.6%, P = 0.017). During the follow-up, the CBDS recurrence rate within 2 years was significantly lower in the EPLBD group than in the control group (21.1% [19/90] vs 36.7% [33/90], relative risk 0.58, 95% confidence interval 0.36-0.93, P = 0.021). At a median follow-up of approximately 56 months, CBDS recurrence was found in 34.4% of the patients (31/90) in the EPLBD group and 51.1% (46/90) in the control group (hazard ratio 0.57, 95% confidence interval 0.36-0.89, P = 0.012). Multiple recurrences (≥2) were also decreased in the EPLBD group (4.4% vs 18.9%, P = 0.020). DISCUSSION: During the long-term follow-up, nearly half of the patients with recurrent CBDS experienced stone recurrence after traditional ERCP. Our study was the first to show that EPLBD effectively reduced the recurrence of CBDS.

Difficult biliary cannulation in ERCP procedures with or without trainee involvement: a comparative study.

BACKGROUND: The 5-5-1 criteria (> 5 minutes - 5 cannulation attempts - 1 unintended pancreas duct cannulation) were proposed by the European Society of Gastrointestinal Endoscopy to define difficult biliary cannulation. However, the criteria may be inappropriate for trainee-involved procedures. We developed criteria for difficult cannulation in trainee-involved procedures. METHODS: Patients undergoing biliary cannulation with or without trainee involvement were eligible. Procedures that might be too easy (e. g. fistula) or too difficult (e. g. altered anatomy) were excluded. The primary outcome was difficult cannulation, defined as cannulation time, attempts, or inadvertent pancreatic duct (PD) cannulation exceeding the 75 % percentile of each variable. Propensity score matching (PSM) analysis was used. RESULTS: After PSM, there were 1596 patients in each group. Trainee-involved procedures had longer median (interquartile range [IQR]) cannulation time (7.5 [2.2-15.3] vs. 2.0 [0.6-5.2] minutes), and more attempts (5 [2-10] vs. 2 [1-4]) and inadvertent PD cannulation (0 [0-2] vs. 0 [0-1]) vs. procedures without trainee involvement (all P < 0.001). The 15-10-2 criteria for difficult cannulation were proposed for trainee-involved cannulation and the 5-5-1 criteria were nearly confirmed for cannulation without trainee involvement. The proportions of difficult cannulation using these respective criteria were 35.5 % (95 % confidence interval [CI] 33.2 %-37.9 %) and 31.8 % (95 %CI 29.5 %-34.2 %), respectively (odds ratio 1.18 [95 %CI 1.02-1.37]). Incidences of post-ERCP pancreatitis following difficult cannulation were comparable (7.8 % [95 %CI 5.7 %-10.3 %] vs. 9.8 % [95 %CI 7.4 %-12.8 %], respectively). CONCLUSION: By using the 75 % percentiles as cutoffs, the proposed 15-10-2 criteria for difficult cannulation could be appropriate in trainee-involved procedures.

Water exchange-assisted versus carbon dioxide-insufflated single-balloon enteroscopy: a randomized controlled trial.

BACKGROUND: Single-balloon enteroscopy (SBE) is a valuable but difficult modality for the diagnosis and treatment of small-bowel disease. The water exchange method has the advantage of facilitating intubation during colonoscopy. Here, we evaluated the effects of water exchange on procedure-related variables related to SBE. METHODS: This randomized controlled trial was conducted in a tertiary-care referral center in China. Patients due for attempted total enteroscopy were randomly allocated to undergo water exchange-assisted (water exchange group) or carbon dioxide-insufflated enteroscopy (CO2 group). All patients were planned to undergo both anterograde and retrograde procedures. The primary outcome was the total enteroscopy rate. Secondary outcomes included the maximal insertion depth, positive findings, procedural time, and adverse events. RESULTS: In total, 110 patients were enrolled, with 55 in each group. Baseline characteristics between the two groups were comparable. Total enteroscopy was achieved in 58.2 % (32/55) of the water exchange group and 36.4 % (20/55) of the control group (P = 0.02). The mean (standard deviation) estimated intubation depth was 521.2 (101.4) cm in the water exchange group and 481.6 (95.2) cm in the CO2 group (P = 0.04). The insertion time was prolonged in the water exchange group compared with the CO2 group (178.9 [45.1] minutes vs. 154.2 [27.6] minutes; P < 0.001). Endoscopic findings and adverse events were comparable between the two groups. CONCLUSIONS: The water exchange method improved the total enteroscopy rate and increased the intubation depth during SBE. The use of water exchange did not increase the complications of enteroscopy.

Efficacy and safety of ERCP in patients with situs inversus totalis: multicenter case series and literature review.

BACKGROUND: Endoscopic retrograde cholangiopancreatography (ERCP) in patients with situs inversus totalis (SIT) is rarely understood due to its rarity. Patient position and endoscope manipulation were the main concerns in published case reports. The aim of this study was to investigate the efficacy and safety of ERCP in SIT patients. METHODS: Patients with SIT who underwent ERCP were enrolled in nine endoscopic centers in China. ERCP procedural details and complications in SIT patients were retrieved from electronic medical record. The data was retrospectively analyzed. RESULTS: From 2011 to 2021, totally 14 patients with SIT undergoing ERCP were identified. The mean age was 56.8 years old and the male-female ratio was 5:2. The main indication for ERCP was common bile duct stones (13/14, 92.9%). All procedure were performed by experienced endoscopists. 21.4% (3/14) of patients were under regular position (prone), while 78.6% under modified position (supine, left or right lateral). Difficult cannulation was occurred in 71.4% (10/14) of patients. The rate of successful cannulation was 85.7% (12/14). Complication occurred in 3 patients (3/14, 21.4%), including 1 bleeding, 1 pneumonia and 1 acute myocardial infarction. No post-pancreatitis or death happened. Compared to patients in modified position, those in prone position had numerically less successful cannulations (66.7% vs. 90.9%) and higher adverse events (33.3% vs. 18.2%). CONCLUSIONS: ERCP in patient with SIT is challenging even for experienced endoscopists, modified patient positions might have potential benefits concerning more successful cannulations and less complications. More case experiences are need for comprehensive understanding of ERCP in patients with SIT.

Functional dyspepsia symptom diary is correlated with other questionnaires and associated with severity in patients with functional dyspepsia: a multicenter, prospective observational study.

BACKGROUND AND AIM: Functional dyspepsia symptom diary (FDSD) is a newly designed questionnaire of functional dyspepsia (FD). The relationships between FDSD and other FD-related questionnaires and patient-reported severity remain unclear. This study aims to investigate the correlations between FDSD and other questionnaires and to determine the relationships between FDSD and FD severity. METHODS: Consecutive outpatients with FD were prospectively enrolled in four tertiary hospitals. All patients were evaluated by six FD-related questionnaires, including FDSD, Dyspepsia Symptom Severity Index (DSSI), Gastrointestinal Symptom Rating Scale, Short-Form Nepean Dyspepsia Index, and Hamilton Depression and Anxiety Scale (HAMD and HAMA). The severity of FD was also graded as mild, moderate, and severe by patients themselves. Correlations between different scores were assessed by Spearman correlation coefficient (ρ), and risk factors for patient-reported severity were identified. RESULTS: For 512 enrolled FD patients, the overall median FDSD score was 19 (2-42). FDSD was well correlated with DSSI (ρ = 0.64) and fairly correlated with the other four scores (ρ = 0.32-0.55) (all P < 0.001). Mild, moderate, and severe FD were reported by 18.5%, 55.9%, and 25.6% of patients, respectively. There were seven factors associated with the severe FD, including education level, duration, and subtypes of FD, prior treatment, FDSD, HAMD, and HAMA scores (all P < 0.10). FDSD ≥ 20 (odds ratio [OR] 3.3, 95% confidence interval [CI]: 2.0-5.2, P < 0.001) and HAMD ≥ 13 (OR 2.9, 95% CI: 1.8-4.6, P < 0.001) were independently associated with patient-reported severe FD. CONCLUSIONS: This study firstly revealed that the newly developed FDSD correlated with other FD-related questionnaires. FDSD ≥ 20 and HAMD ≥ 13 were independently associated with severe FD reported by patients (clinicaltrials.gov number: NCT04953975).

Combination prevention of post-endoscopic retrograde cholangiopancreatography pancreatitis in patients undergoing double-guidewire assisted biliary cannulation: A case-control study with propensity score matching.

BACKGROUND AND AIM: Rectal indomethacin and pancreatic duct stenting (PDS) are recommended for the prevention of post-endoscopic retrograde cholangiopancreatography pancreatitis (PEP). However, the effects of the combination of the two methods on preventing PEP are controversial. We hypothesized that some group of difficult patients might benefit from the combination of indomethacin plus PDS (IP) compared with indomethacin alone (IN). METHODS: Patients with native papilla who underwent endoscopic retrograde cholangiopancreatography in eight tertiary hospitals were screened. They were enrolled if the cannulation proved difficult and post-procedure indomethacin was administered. Propensity score matching (PSM) was used to balance the baseline characteristics between IP and IN groups. The primary outcome was PEP. RESULTS: Among 4456 patients with available cannulation-related data, 1889 (42.4%) patients had difficult cannulation and received indomethacin. After PSM, both IP and IN groups included 332 patients. PEP was comparable between the two groups (12.7% vs 10.2%, P = 0.329). By subgroup analysis, the PEP rate was found to be lower in the IP group than in the IN group (7.3% vs 18.2%, P = 0.026) in patients undergoing double-guidewire technique (DGT). The results of an additional analysis using PSM in DGT patients were consistent with the subgroup analysis results (7.8% vs 19.4%, P = 0.036). CONCLUSIONS: The current study indicated that the combined prevention of PEP with indomethacin plus PDS was useful in PEP prevention in patients undergoing DGT. Other groups of patients with difficult cannulation may not benefit from the combination strategy.

Inhibition of PAD4 enhances radiosensitivity and inhibits aggressive phenotypes of nasopharyngeal carcinoma cells.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is a tumor deriving from nasopharyngeal epithelium. Peptidyl-arginine deiminase 4 (PAD4) is a vital mediator of histone citrullination and plays an essential role in regulating disease process. Radiotherapy is an essential method to treat NPC. In this research, we explored the effect of PAD4 on NPC radiosensitivity. METHODS: We enrolled 50 NPC patients, established mice xenograft model, and purchased cell lines for this study. Statistical analysis and a series of experiments including RT-qPCR, clonogenic survival, EdU, Transwell, and wound healing assays were done. RESULTS: Our data manifested that PAD4 (mRNA and protein) presented a high expression in NPC tissues and cells. GSK484, an inhibitor of PAD4, could inhibit activity of PAD4 in NPC cell lines. PAD4 overexpression promoted the radioresistance, survival, migration, and invasion of NPC cells, whereas treatment of GSK484 exerted inhibitory effects on radioresistance and aggressive phenotype of NPC cells. Additionally, GSK484 could attenuate the effect of PAD4 of NPC cell progression. More importantly, we found that GSK484 significantly inhibited tumor size, tumor weight and tumor volume in mice following irradiation. CONCLUSIONS: PAD4 inhibitor GSK484 attenuated the radioresistance and cellular progression in NPC.

PAD4 inhibitor promotes DNA damage and radiosensitivity of nasopharyngeal carcinoma cells.

Peptidylarginine deiminases 4 (PAD4), a kind of enzyme capable of converting protein arginine or mono-methylarginine into citrulline, has been identified to display a key role in diverse diseases. Radiotherapy is frequently used in nasopharyngeal carcinoma (NPC) treatment and induces DNA double strand breaks. In this study, whether PAD4 inhibitor YW3-56 affects the radiosensitivity of NPC cells was explored. RT-qPCR, immunofluorescence, western blot, clonogenic survival, and flow cytometry assays were used to assess the function of PAD4 and YW3-56 in NPC. We found the upregulation of PAD4 expression in NPC cells. PAD4 overexpression suppressed NPC cell apoptosis and promoted cell cycle, while PAD4 depletion had an opposite result. Moreover, the survival of NPC cells after irradiation was increased by overexpression of PAD4. PAD4 overexpression inhibited DNA damage and sensitivity of NPC cells to irradiation. Functional assays showed that YW3-56 treatment promoted DNA damage, apoptosis, and radiosensitivity of NPC cells. Importantly, YW3-56 treatment inhibited tumor growth in vivo. Overall, this study revealed the efficacy of PAD4 inhibitor YW3-56 in promoting sensitivity of NPC cells to irradiation.

Relationship between papilla-related variables and post endoscopic retrograde cholangiopancreatography pancreatitis: A multicenter, prospective study.

BACKGROUND AND AIM: Papilla with hooknose or long protruding shape may increase the difficulty of cannulation during endoscopic retrograde cholangiopancreatography (ERCP). However, the relationship between papilla anatomy and complications of ERCP has not been fully understood. We aimed to investigate the effect of major duodenal papilla morphology on post-ERCP pancreatitis (PEP) and the procedure of cannulation. METHODS: Patients with native papilla who underwent ERCP were recruited to this multicenter study. Papilla-related variables were collected, including the length of long axis (L), short axis (S) and opening width (OW), transverse fold, periampullary diverticulum (PAD), papilla location, orientation, swelling, and presence of duodenal stenosis. Demographic data and the procedure of cannulation were also prospectively evaluated. The primary outcome was PEP incidence. Multivariate analysis was used to identify high risk factors for PEP. RESULTS: Six hundred and fifty-eight patients were enrolled. Overall PEP incidence was 4.7% (31/658). The papilla of patients complicated with PEP had higher long to short axis (L/S) ratio (odds ratio [OR] 3.84, 95% confidence interval [CI]: 1.37-10.74, P = 0.010), higher long axis to opening width (L/OW) ratio (OR 1.35, 95%CI: 1.06-1.71, P = 0.014), more transverse folds (OR 2.53, 95%CI: 1.02-6.26, P = 0.044), and less periampullary diverticulum (OR 0.21, 95%CI: 0.06-0.70, P = 0.011). Multivariate analysis revealed that the indication of common bile duct stones, normal bilirubin, inadvertent pancreatic duct cannulation > 1, L/S ratio ≥ 1.5, and absence of PAD were independent risk factors for PEP. CONCLUSION: Besides patient-related and procedure-related factors, papilla-related variables, such as L/S ratio and PAD, can be considered as a third type of factors associated with PEP (Clinicaltrials.gov number: NCT03550768).

Learning curve of double-guidewire technique by trainees during hands-on endoscopic retrograde cholangiopancreatography training.

BACKGROUND AND AIMS: Double-guidewire technique (DWT) has been successfully performed by experts in difficult biliary cannulation as an advanced technique. This study aimed to define the learning curve and safety of DWT by trainees during hands-on endoscopic retrograde cholangiopancreatography (ERCP) training. METHODS: Patients were eligible for inclusion in the study if the biliary cannulation was difficult and the pancreatic duct was inadvertently cannulated. DWT was performed by two trainees randomly under trainers' guidance. The primary outcome was the success rate of DWT biliary cannulation of trainees. Cumulative sum analysis was used to generate visual learning curves. RESULTS: A total of 60 patients with difficult cannulation were enrolled. The main indications for ERCP were common bile duct stones (65%) and biliary stricture (31.7%). The learning curve analysis showed that to achieve a 70% rate of successful DWT, 12 procedures were needed for trainee A and 15 for trainee B. Higher targeted success rate of DWT could be achieved if the number of DWT procedures increased. Compared with the early stage of learning DWT (case 1 to 15 for each trainee), trainees had significantly higher DWT success rate in the late stage (36.7% [11/30] vs 80% [24/30], P = 0.001). The final success rate of cannulation was 98.3% (59/60). The overall rate of post-ERCP pancreatitis and adverse events was 6.7% (4/60) and 8.3% (5/60), respectively. CONCLUSIONS: Double-guidewire technique was safely performed by two novel trainees during hands-on ERCP training. Fifteen procedures may be enough for trainees to achieve the competency of performing DWT. (Clinicaltrials.gov number: NCT03707613).

Risk Factors Associated with Inadequate Bowel Preparation in Patients with Functional Constipation.

BACKGROUND: Constipation is a common reason of poor bowel preparation, which negatively influences the quality of colonoscopy. Risk factors for inadequate bowel preparation in constipated patients remain unclear. AIMS: This study aimed to investigate the high-risk factors that might influence the quality of bowel preparation in patients with functional constipation. METHODS: Consecutive patients with functional constipation who underwent colonoscopy between June 2016 and April 2017 were enrolled. A standard split dose of 4 l polyethylene glycol was used for bowel preparation. Patient- and procedure-related parameters were recorded. The primary outcome was an adequate rate of bowel preparation. Risk factors for inadequate bowel preparation were screened by multivariate logistic regression analysis. RESULTS: A total of 199 patients were included. Adequate bowel preparation was found in 62.8% (125/199) of patients. At multivariate analysis, Bristol stool form scale (BSFS) 1 [odds ratio (OR) 2.73, 95% confidence interval (CI) 1.26-5.90; P = 0.011], rectal pain score during defecation < 2 (OR 4.14, 95% CI 1.22-13.97; P = 0.022), and starting-to-defecation interval ≥ 4 h (OR 3.83, 95% CI 1.34-10.91; P = 0.012) were risk factors for inadequate bowel preparation in patients with constipation. For patients with no, 1, 2, or 3 risk factors, the rates of inadequate bowel preparation were 11%, 23%, 49%, and 65%, respectively. CONCLUSIONS: With the standard preparation regime, > 1/3 of patients with functional constipation had inadequate bowel cleansing. BSFS 1, rectal pain score during defecation < 2, and starting-to-defecation interval ≥ 4 h were identified as independent risk factors for inadequate bowel preparation in constipated patients. TRIAL REGISTRATION: ClinicalTrials.gov number NCT02842411.

Rectal Indomethacin and Spraying of Duodenal Papilla With Epinephrine Increases Risk of Pancreatitis Following Endoscopic Retrograde Cholangiopancreatography.

BACKGROUND & AIMS: Rectal indomethacin and spraying of the duodenal papilla with epinephrine might reduce the incidence of pancreatitis after endoscopic retrograde cholangiopancreatography (ERCP). We performed a randomized trial to compare the effects of the combination of indomethacin and epinephrine (IE) vs indomethacin plus saline (IS) in prophylaxis of post-ERCP pancreatitis (PEP). METHODS: We performed a double-blind trial at 10 centers in China, from February 2017 to October 2017, of 1158 patients with native papilla undergoing ERCP. The patients were assigned randomly to groups given IE (n = 576) or IS (n = 582). All patients received a single dose of rectal indomethacin within 30 minutes before ERCP; 20 mL of dilute epinephrine (IE group) or saline (IS group) then was sprayed on the duodenal papilla at the end of ERCP. The primary outcome was the incidence of overall PEP. Data were analyzed on an intention-to-treat principle. RESULTS: The study was terminated at the interim analysis for safety concerns and futility. The groups had similar baseline characteristics. PEP developed in 49 patients in the IE group (8.5%) and in 31 patients in the IS group (5.3%) (relative risk, 1.60, 95% CI, 1.03-2.47; P = .033). There were no significant differences between groups in proportions of patients with postsphincterotomy bleeding (2.1% in the IE group and 1.5% in the IS group) and biliary infection (1.2% in the IE group and 2.2% in the IS group). CONCLUSIONS: In a randomized trial, we found the combination of rectal indomethacin with papillary epinephrine spraying increased the risk of PEP compared with indomethacin alone. Spray epinephrine should not be used with rectal indomethacin for prevention of post-ERCP pancreatitis. ClincialTrials.gov no: NCT03057769.