Design, synthesis, and pharmacological evaluation of novel benzothiazole derivatives targeting LCK in acute lymphoblastic leukemia.

Lymphocyte-specific protein tyrosine kinase (LCK), a member of the Src family of tyrosine kinases, is implicated in the pathogenesis of almost all types of leukemia via T cells activation and signal transduction. LCK is highly expressed in acute lymphoblastic leukemia (ALL), and knockdown of the LCK gene can significantly inhibit the proliferation of leukemia cell lines. Here, we designed and synthesized a series of benzothiazole derivatives as novel LCK inhibitors using both docking-based virtual screening and activity assays for structural optimization. Among these compounds, 7 m showed a strong inhibitory activity in the proliferation of leukemia cell lines and LCK kinase activity. Moreover, we found that compound 7 m could induce apoptosis while simultaneously blocking cell cycle via decreasing its phosphorylation at Tyr394 of the LCK. Collectively, these findings shed new light on compound 7 m that would be utilized as a promising drug candidate with apoptosis-triggered and cell cycle arrest activities for the future ALL therapy.

A long-term follow-up study of gastric peroral endoscopic myotomy (G-POEM) in a large cohort of patients with postsurgical gastroparesis.

INTRODUCTION: Postoperative gastroparesis occurs after surgeries which affect the upper digestive tract. Gastric peroral endoscopic myotomy (G-POEM) is a treatment for postoperative gastroparesis. The present study boasts the long-term efficacy and safety of G-POEM in a large cohort of patients. PATIENTS AND METHODS: Gastroparesis Cardinal Symptom Index (GCSI) and Gastroesophageal Reflux Disease Questionnaire (GERDQ) were utilized for the assessment of postsurgical gastroparesis symptoms. Gastroscope was used to observe the anastomotic site. Three-dimensional ultrasound was used to measure the morphological structure of the gastric antrum and pylorus tube. Gastric emptying time was calculated by analyzing the volume change of gastric antrum. RESULTS: Significant clinical effectiveness of G-POEM was observed. The GCSI score, including each subscale score, showed significant decrease after G-POEM. Before G-POEM, there was a negative correlation between GCSI score and the inner diameter of pylorus, as well as a positive correlation with the length of pyloric tube. The similar results were found in the scores of nausea/vomiting and postprandial fullness/early satiety subscales. No correlation was observed between GCSI score and the emptying time, nor between the emptying time and the parameters of antrum morphology. After G-POEM, no correlation was found between GCSI (including subscales) score, the emptying time, and the parameters of antrum morphology. Patients who exhibited as clinical non-responders often accompanied with GERD symptoms. After G-POEM, the score of GERDQ decreased significantly. Either before or after G-POEM, no correlation was noticed between GERDQ scores, the emptying time and the parameters of antrum morphology. CONCLUSION: The technique of G-POEM was demonstrated as a minimally invasive approach with the long-term efficacy and safety in therapying postoperative gastroparesis.

Comparison of 180° anti-reflux mucosectomy versus 270° anti-reflux mucosectomy for treatment of refractory gastroesophageal reflux disease: a retrospective study.

BACKGROUND: Anti-reflux mucosectomy (ARMS) is a novel endoscopic treatment for refractory gastroesophageal reflux disease (rGERD). Several studies have validated its safety and effectiveness, but postoperative dysphagia remains in concern. Since the influence of different resection ranges on efficacy and complications of ARMS has rarely been studied, this study aimed to compare outcomes of 180°ARMS and 270°ARMS in treatment of rGERD. METHODS: This study was conducted from August 2017 to September 2020. 39 eligible patients underwent either 180° ARMS or 270° ARMS and followed up at 6 months postoperation. Primary outcome measure was assessed by Gastroesophageal Reflux Disease Questionnaire (GERD-Q). Secondary outcomes included quality of life, PPI use, gastroesophageal flap valve grade, presence of reflux esophagitis, acid exposure time (AET), distal contractile integral (DCI), and integrated relaxation pressure (IRP) measured by high-resolution manometry (HRM) and complication rate. Per-protocol analysis was performed. RESULTS: Among 39 patients, 18 underwent 180° ARMS, while 21 underwent 270° ARMS. At postoperative 6 months follow-up period, primary outcome showed no significant difference between two groups (p = 0.34). Similarly, no significant difference was demonstrated between groups regarding most secondary outcomes except for fewer complaints of newly dysphagia in 180° ARMS group. No other serious complications were observed in both groups. CONCLUSION: Although 180° ARMS and 270° ARMS could be equally effective for treatment of rGERD, 180° ARMS might be more recommended due to lower incidence of newly post-procedural dysphagia.

Feasibility, safety, and long-term efficacy of gastric peroral endoscopic myotomy (G-POEM) for postsurgical gastroparesis: a single-center and retrospective study of a prospective database.

BACKGROUND: Postsurgical gastroparesis is recognized as a gastrointestinal dysfunction syndrome following foregut surgery. Gastric peroral endoscopic myotomy (G-POEM) is suggested as a minimally invasive therapy for gastroparesis. But the long-term efficacy and safety of G-POEM in treating postsurgical gastroparesis are rarely explored. METHODS: The primary outcomes included the symptomatic improvement based on gastroparesis cardinal symptoms index (GCSI) and the improvement of gastric emptying. The secondary outcomes included the improvement of gastroesophageal reflux symptoms and complications of G-POEM. RESULTS: The severity of postsurgical gastroparesis was not associated with the onset time and the course of the disease. G-POEM significantly reduced GCSI throughout the follow-up period (p < 0.0001). For different anastomotic site, a significant improvement of GCSI was found at 6 month post-G-POEM (F4,165 = 74.18, p < 0.0001). Subscale analysis of GCSI showed that nausea/vomiting, post-prandial fullness/early satiety, and bloating were improved significantly at 6-month post-G-POEM (p < 0.0001, respectively). Half-emptying and whole-emptying time were significantly shortened in patients with different anastomotic site post-G-POEM (half-emptying time: F3,174 = 65.44, p < 0.0001; whole-emptying time: F3,174 = 54.85, p < 0.0001). The emptying of ioversol was obviously accelerated after G-POEM. GCSI wasn't related to pyloric length, pyloric diameter, and thickness of pyloric wall. GERDQ was also used to evaluate the clinical efficacy of G-POEM. For each time points, GERDQ didn't differ significantly in patients with different anastomotic site (F4,104 = 0.8075, p = 0.5231). For patients with different anastomotic site, GERDQ was improved significantly at different time points (F4,104 = 59.11, p < 0.0001). The higher the esophageal anastomotic site was, the faster G-POEM improved the symptoms of gastroesophageal reflux. No one required re-hospitalization for any complication. CONCLUSION: G-POEM is a minimally invasive therapy with long-term effectiveness and safety in treating postsurgical gastroparesis.

Peptoids advance multidisciplinary research and undergraduate education in parallel: Sequence effects on conformation and lipid interactions.

Peptoids are versatile peptidomimetic molecules with wide-ranging applications from drug discovery to materials science. An understanding of peptoid sequence features that contribute to both their three-dimensional structures and their interactions with lipids will expand functions of peptoids in varied fields. Furthermore, these topics capture the enthusiasm of undergraduate students who prepare and study diverse peptoids in laboratory coursework and/or in faculty led research. Here, we present the synthesis and study of 21 peptoids with varied functionality, including 19 tripeptoids and 2 longer oligomers. We observed differences in fluorescence spectral features for 10 of the tripeptoids that correlated with peptoid flexibility and relative positioning of chromophores. Interactions of representative peptoids with sonicated glycerophospholipid vesicles were also evaluated using fluorescence spectroscopy. We observed evidence of conformational changes effected by lipids for select peptoids. We also summarize our experiences engaging students in peptoid-based projects to advance both research and undergraduate educational objectives in parallel.

Melatonin protects the esophageal epithelial barrier by suppressing the transcription, expression and activity of myosin light chain kinase through ERK1/2 signal transduction.

BACKGROUND/AIMS: Dilated intercellular space (DIS) contributes to the pathophysiology of gastroesophageal reflux disease (GERD). Melatonin protects the esophageal mucosa; however, the mechanisms underlying that protection remain unclear. METHODS: Transmission electron microscopy (TEM) was used to evaluate the intercellular spaces in the esophageal epithelium of GERD patients. The Het-1A monolayer barrier function was investigated by measuring transepithelial resistance (TER) and FITC-dextran paracellular permeation. The activity of MLCK was represented by MLC phosphorylation. The expression and phosphorylation of MLCK, MLC and ERK were examined by western blot analysis. RESULTS: The expression and activity of MLCK and ERK phosphorylation were increased in the esophageal epithelium. The increased expression and activity of MLCK was correlated with dilated intercellular spaces. Upon acid treatment, the Het-1A monolayer permeability was increased. When the Het-1A monolayer was pretreated with melatonin and PD98059 before the acid incubation, the permeability and the expression and phosphorylation of MLCK and ERK decreased. CONCLUSION: Melatonin protects the esophageal epithelial barrier by suppressing the transcription, translation and activity of MLCK through ERK1/2 signal transduction. These findings provide a better understanding of the potential clinical application of melatonin in GERD treatment.

Mechanism-Driven Design of Multispecific Antibodies for Targeted Disease Treatment.

Antibody-based therapeutics constitute a rapidly growing class of pharmaceutical compounds. However, monoclonal antibodies, which specifically engage only one target, often lack the mechanistic intricacy to treat complex diseases. To expand the utility of antibody therapies, significant efforts have been invested in designing multispecific antibodies, which engage multiple targets using a single molecule. These efforts have culminated in remarkable translational progress, including nine US Food and Drug Administration-approved multispecific antibodies, with countless others in various stages of preclinical or clinical development. In this review, we discuss several categories of multispecific antibodies that have achieved clinical approval or shown promise in earlier stages of development. We focus on the molecular mechanisms used by multispecific antibodies and how these mechanisms inform their customized design and formulation. In particular, we discuss multispecific antibodies that target multiple disease markers, multiparatopic antibodies, and immune-interfacing antibodies. Overall, these innovative multispecific antibody designs are fueling exciting advances across the immunotherapeutic landscape. Expected final online publication date for the Annual Review of Chemical and Biomolecular Engineering , Volume 15 is June 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Multiparatopic antibodies induce targeted downregulation of programmed death-ligand 1.

Programmed death-ligand 1 (PD-L1) drives inhibition of antigen-specific T cell responses through engagement of its receptor programmed death-1 (PD-1) on activated T cells. Overexpression of these immune checkpoint proteins in the tumor microenvironment has motivated the design of targeted antibodies that disrupt this interaction. Despite clinical success of these antibodies, response rates remain low, necessitating novel approaches to enhance performance. Here, we report the development of antibody fusion proteins that block immune checkpoint pathways through a distinct mechanism targeting molecular trafficking. By engaging multiple receptor epitopes on PD-L1, our engineered multiparatopic antibodies induce rapid clustering, internalization, and degradation in an epitope- and topology-dependent manner. The complementary mechanisms of ligand blockade and receptor downregulation led to more durable immune cell activation and dramatically reduced PD-L1 availability in mouse tumors. Collectively, these multiparatopic antibodies offer mechanistic insight into immune checkpoint protein trafficking and how it may be manipulated to reprogram immune outcomes.

A New Method for Inversion of Dam Foundation Hydraulic Conductivity Using an Improved Genetic Algorithm Coupled with an Unsaturated Equivalent Continuum Model and Its Application.

Seepage is a main cause of dam failure, and its stability analysis is the focus of a dam's design, construction, and management. Because a geological survey can only determine the range of a dam foundation's hydraulic conductivity, hydraulic conductivity inversion is crucial in engineering. However, current inversion methods of dam hydraulic conductivity are either not accurate enough or too complex to be directly used in engineering. Therefore, this paper proposes a new method for the inversion of hydraulic conductivity with high application value in hydraulic engineering using an improved genetic algorithm coupled with an unsaturated equivalent continuum model (IGA-UECM). This method is implemented by a new code that fully considers engineering applicability. In addition to overcoming the premature convergence shortcomings of traditional genetic algorithms, it converges faster than Bayesian optimization and tree-structured Parzen estimator inversion algorithms. This method is verified by comparing the water head from drilling exploration and inversion. The results of the inversion are used to study the influence of a cement grouting curtain layout scheme on the seepage field of the Hami concrete-face rockfill dam in China, which is used as an engineering application case of the IGA-UECM. The law of the seepage field is reasonable, which verifies the validity of the IGA-UECM. The new inversion method of hydraulic conductivity and the proposed cement grouting curtain layout in this study offer possible strategies for the design, construction, and management of concrete-face rockfill dams.

Antibacterial Nanocellulose-TiO2/Polyester Fabric for the Recyclable Photocatalytic Degradation of Dyes.

In this paper, we report an antibacterial, recyclable nanocellulose-titanium dioxide/polyester nonwoven fabric (NC-TiO2/PET) composite for the highly efficient photocatalytic degradation of dyes. The NC-TiO2 was loaded onto the surface of flexible PET nonwoven fabric through a simple swelling and dipping method. The NC-TiO2 in the particle size range of ~10 nm were uniformly attached to the surface of the PET fibers. The NC-TiO2/PET composite has the ability to achieve the stable photocatalytic degradation of dyes and presents antibacterial properties. The degradation rates to methylene blue (MB) and acid red (AR) of the NC-TiO2/PET composite reached 90.02% and 91.14%, respectively, and the inhibition rate of Escherichia coli was >95%. After several rounds of cyclic testing, the photocatalytic performance, antibacterial performance, and mechanical stability of the NC-TiO2/PET composite remained robust.

Experimental Investigation on Seepage Characteristics of Clay-Structure Interface after Shear Deformation.

There exist shear and seepage behaviors on the interface between clay core and concrete slab in clay core dams. In order to investigate the seepage characteristics of the clay-structure interface after shear deformation, a shear-seepage test system is proposed, in which the seepage direction is perpendicular to the shear direction. The shear test and shear-seepage test are performed on clay-metal and clay-mortar interfaces under different normal stresses (100, 200, 400, 800, and 1600 kPa). The shear stress-deformation curves of two clay-structure interfaces exhibit softening behavior and residual friction behavior. The interface roughness can enhance peak and residual shear strength and increase peak displacement. The shear-seepage test results show that specimen permeability decreases first and then increases to a stable value as shear deformation increases under low normal stress, while it decreases continuously and then retains stability under high normal stress. The interface roughness enhances specimen permeability under low normal stress, whereas it has a weak effect on specimen permeability under high normal stress. Compared with initial permeability, shear deformation reduces specimen permeability rather than raise it. The ratio of stabilized permeability coefficient to initial value ranges from 0.6 to 0.8. The clay-structure interface still has a good resistance to seepage failure after shear deformation. The shear dilation features and interface pore decrease caused by shear behavior are the internal attributions of clay-structure specimen permeability evolution.

In situ synthesis of TiO2/NC on cotton fibers with antibacterial properties and recyclable photocatalytic degradation of dyes.

A cotton fabric/titanium dioxide-nanocellulose (TiO2-Cot.) flexible and recyclable composite material with highly photocatalytic degradation of dyes and antibacterial properties was synthesized. During the preparation process, nano-TiO2 particles were synthesized through an in situ strategy and grown on cotton fiber, and were wrapped with cellulose nanocrystals (NC). The prepared TiO2-Cot. was characterized by field emission scanning electron microscopy (FESEM), X-ray diffraction (XRD) and Fourier transform infrared spectroscopy (FTIR). The SEM and EDS results showed that nano-TiO2 particles were evenly distributed on the fiber surface. The prepared TiO2@Cot. has excellent photocatalytic efficiency of 95.68% for MB and 92.77% for AR under weak ultraviolet irradiation over 6 h. At the same time, it has excellent antibacterial activity against S. aureus and E. coli. The stability and reusability of the materials were also investigated.

Evaluation of gastric emptying in patients with gastroparesis by three-dimensional ultrasound.

BACKGROUND: To diagnose gastroparesis, it is necessary to assess gastric emptying accurately. This study aims to investigate the role of three-dimensional ultrasonography (3-D US) on the measurement of gastric volume to evaluate gastric accommodation in healthy patients. METHODS: In this study, 21 volunteers, 46 patients with diabetic gastroparesis (DG), and 22 patients with postsurgical gastroparesis (PSG) underwent 3-D US after oral administration of 250 mL gastrointestinal contrast at 2, 30, 60, and 90 min. The volume of the contrast agent in the stomach was then calculated using the virtual organ computer-aided analysis (VOCAL) (Virtual Organ Computer-aided AnaLysis, General Electric Medical Systems, Kretztechnik, Zipf, Austria). RESULTS: In the DG group, the gastric residue volumes at postprandial 60 and 90 min were significantly higher than those in the healthy group (P<0.05), and the areas under the receiver operating characteristic (ROC) curve of these parameters were 0.830 and 0.957, respectively. There were significant differences between the PSG and healthy groups at 60 and 90 min; however, the AUC of gastric residue at 90 min (0.955) was higher than the AUC at 60 min (0.697). CONCLUSIONS: Therefore, this study showed that the 3-D US is a powerful tool for assessing gastric emptying and provides a new strategy for diagnosing gastroparesis.

Diverse N-Substituted Azole-Containing Amino Acids as Building Blocks for Cyclopeptides.

The preparation of 16 oxazole- or thiazole-containing amino esters bearing a wide array of N-substitution is reported. These were accessed in 40-92% yield via an AgClO4-promoted substitution reaction between a primary amine and a chloromethyl-functionalized thiazole or oxazole. These new synthetic building blocks will be useful for the preparation of new cyclopeptide analogues bearing heterocyclic backbone modifications. Four macrocyclic N-substituted oligoamides that include thiazole or oxazole heterocycles were obtained, following cyclooligomerization reactions of azole-modified N-substituted amino acids.

Clopidogrel-Induced Gastric Injury in Rats is Attenuated by Stable Gastric Pentadecapeptide BPC 157.

AIM: Although Clopidogrel is safe in healthy volunteers, it can induce recurrence of gastric ulcers in high-risk patients. Here, we investigated the protective effect of the natural product, stable gastric pentadecapeptide 157 (BPC 157) on Clopidogrel-induced gastric injury. METHODS: We used acetic acid to induce gastric ulcer in Sprague Dawley rats. Clopidogrel alone or in combination with BPC 157 or L-NAME (nitric oxide system blockade) were administered after healing of acetic acid-induced ulcer. One percent methylcellulose solution was used as control. Ulcer recurrence rate and the ulcer index were compared between these groups. Gastric mucosal apoptosis rate, microscopic inflammation activity and angiogenesis markers vascular endothelial growth factor A (VEGF-A) and CD34 were examined by TUNEL, histological evaluations (HE) and immunohistochemistry (IHC). Pathways involved, expressions of endoplasmic reticulum (ER) stress apoptosis marker CHOP, angiogenic markers VEGF-A and its receptor VEGFR1, and endothelial NO synthase (eNOS) were all analyzed by Western blot. RESULTS: This study indicated that Clopidogrel significantly induced the gastric ulcers recurrence, severe inflammation and ER stress related apoptosis of the gastric mucosa, suppressed the synthesis of angiogenic markers and eNOS. Furthermore, Clopidrogel intervention resulted in the activation of protein kinase B (AKT) and p38 mitogen-activated protein kinase (p38/MAPK). BPC 157 attenuated the gastric mucosal damage caused by Clopidogrel and reversed these molecular effects. However, NO blockade L-NAME weakened the protective effect and thus the molecular effects of BPC 157 on gastric mucosa. CONCLUSION: In conclusion, these results suggest that BPC 157 inhibited Clopidogrel-induced gastric mucosa injury partially by inhibition of gastric mucosa cell ER stress-mediated apoptosis and inflammation, and promoting gastric mucosa angiogenesis via VEGF-A/VEGFR1 mediated-AKT/p38/MAPK signaling pathways.

Role of MKP-5-p38/MAPK pathway in Clopidogrel-induced gastric mucosal epithelial cells apoptosis and tight junction dysfunction.

Bleeding and delayed healing of gastric ulcer are well-recognized in patients following Clopidorgrel treatment. Our previous studies have shown that endoplasmic reticulum stress (ER) is involved in Clopidogrel-induced gastric mucosal damage through activating p38 mitogen-activated protein kinases (MAPK) pathway. This present study aims to further investigate the role of MAP kinase phosphatase 5 (MKP-5), a MKP known to dephosphorylate and inactivate p38/MAPK, in Clopidogrel-induced gastric mucosal injury and the underlying mechanisms. It shows that MKP-5 is down-regulated at both mRNA and protein levels in the gastric mucosa from bleeding patients who took Clopidogrel over one year. In vitro study using human gastric epithelial cell line GES-1 demonstrates that exposure to Clopidorgrel (1.0-2.0 mM) increases phosphorylation of p38/MAPK and decreases MKP-5 expression simultaneously. Overexpression of MKP-5 promotes GES-1 cell proliferation and reduces apoptosis following Clopidogrel exposure. Interestingly, overexpression of MKP-5 also attenuates Clopidorgrel-induced tight junction (TJ) destruction by down-regulating expression of ER stress-related protein C/EBP homologous protein (CHOP) and tribbles pseudokinase 3 (TRIB3). These three effects, increased proliferation, reduced apoptosis and attenuated TJ destruction, are regulated through inhibited phosphorylation of p38/MAPK signaling pathway. We conclude that MKP-5 is down-regulated in Clopidogrel-induced gastric mucosa injury in vivo and in vitro via phosphorylation and activation of p38/MAPK signaling pathway. Overexpression of MKP-5 reverses Clopidogrel-induced gastric mucosal injury. These findings imply that MKP-5 may be a potential therapeutic target in Clopidogrel-induced gastric mucosal injury and bleeding.

lncRNA PVT1 Promotes Tumorigenesis of Colorectal Cancer by Stabilizing miR-16-5p and Interacting with the VEGFA/VEGFR1/AKT Axis.

Recently, the long noncoding RNA (lncRNA) plasmacytoma variant translocation 1 (PVT1) was reported to be involved in the pathogenesis of several cancers, including human colorectal cancer (CRC). However, the molecular basis for cancer initiation, development, and progression remains unclear. In this study, we observe that upregulated PVT1 is associated with poor prognosis and bad clinicopathological features of CRC patients. In vitro means of PVT1 loss in a CRC cell line inhibit cell proliferation, migration, and invasion. Furthermore, dual-luciferase reporter and RNA pull-down assays indicated that PVT1 binds to miR-16-5p, which has been shown to play strong tumor suppressive roles in CRC. Targeted loss of miR-16-5p partially rescues the suppressive effect induced by PVT1 knockdown. Vascular endothelial growth factor A (VEGFA), a direct downstream target of miR-16-5p, was suppressed by PVT1 knockdown in CRC cells. Overexpression of VEGFA is known to modulate the AKT signaling cascade by activating vascular endothelial growth factor receptor 1 (VEGFR1). We, therefore, show that PVT1 loss combined with miR-16-5p overexpression reduces tumor volume maximally when propagated within a mouse xenograft model. We conclude that the PVT1-miR-16-5p/VEGFA/VEGFR1/AKT axis directly coordinates the response in CRC pathogenesis and suggest PVT1 as a novel target for potential CRC therapy.

Effects of Prebiotics and Synbiotics on Functional Constipation.

The objective was to determine the effects of prebiotics and synbiotics on adults with functional constipation (FC). Medline, Embase and the Cochrane Library were searched for literature published up to February 2015. We selected randomized controlled trials (RCTs) that reported administration of prebiotics or synbiotics to adults with FC. The end points included stool frequency, stool consistency and other symptoms related to constipation. Mean differences (MD) or standard mean differences (SMD) were used for continuous outcomes and risk ratios for discontinuous outcomes using a random-effects model. The Cochrane Risk of Bias Tool was used to determine the quality of the trials. Funnel plots and Egger's test were used to analyze for publication bias. We included 5 RCTs involving 199 patients who were administered prebiotics and 8 RCTs involving 825 patients who were administered synbiotics. Prebiotics increased weekly stool frequency (MD: 1.01bowel movements/week, 95% CI: 0.04-1.99) and improved stool consistency (SMD: -0.59, 95% CI: -1.16 to -0.02). Subgroup analysis showed specific effects for galacto-oligosaccharides on stool frequency, consistency, ease of defecation and abdominal pain. Synbiotics significantly improved stool frequency (MD: 1.15bowel movements/week, 95% CI: 0.58-1.71), consistency (SMD: 0.63, 95% CI: 0.33-0.92) and reduced whole-gut transit time (MD: 13.52, 95% CI: -26.56 to -0.49) in patients with FC. Subgroup analysis showed specific effects for fructo-oligosaccharides and probiotic combinations on stool frequency, consistency, straining defecation and bloating. Galacto-oligosaccharides and synbiotics made up of fructo-oligosaccharides with probiotic combinations may improve stool frequency, consistency and some other symptoms related to constipation.

Association between diabetes mellitus and gastroesophageal reflux disease: A meta-analysis.

AIM: To investigate whether there is a link between diabetes mellitus (DM) and gastroesophageal reflux disease (GERD). METHODS: We conducted a systematic search of PubMed and Web of Science databases, from their respective inceptions until December 31, 2013, for articles evaluating the relationship between DM and GERD. Studies were selected for analysis based on certain inclusion and exclusion criteria. Data were extracted from each study on the basis of predefined items. A meta-analysis was performed to compare the odds ratio (OR) in DM between individuals with and without GERD using a fixed effect or random effect model, depending on the absence or presence of significant heterogeneity. Subgroup analyses were used to identify sources of heterogeneity. Publication bias was assessed by Begg's test. To evaluate the results, we also performed a sensitivity analysis. RESULTS: When the electronic database and hand searches were combined, a total of nine eligible articles involving 9067 cases and 81 968 controls were included in our meta-analysis. Based on the random-effects model, these studies identified a significant association between DM and the risk of GERD (overall OR = 1.61; 95%CI: 1.36-1.91; P = 0.003). Subgroup analyses indicated that this result persisted in studies on populations from Eastern countries (OR = 1.71; 95%CI: 1.38-2.12; P = 0.003) and in younger patients (mean age < 50 years) (OR = 1.70; 95%CI: 1.22-2.37; P = 0.001). No significant publication bias was observed in this meta-analysis using Begg(')s test (P = 0.175). The sensitivity analysis also confirmed the stability of our results. CONCLUSION: This meta-analysis suggests that patients with DM are at greater risk of GERD than those who do not have DM.