Exclusive Enteral Nutrition Orchestrates Immunological Balances as Early as Week 4 in Adult Patients of Crohn's Disease: A Pilot, Open-Lable Study.

BACKGROUND AND AIMS: The efficacy and underlying mechanisms of exclusive enteral nutrition (EEN) in adult patients with Crohn's disease (CD) remain controversial. This study aimed to evaluate the role of EEN in adult patients with CD and to explore the mechanisms from the perspective of immunoregulation. METHODS: This is a prospective, open-label pilot study. Active patients with CD were enrolled and prescribed an amino-acid-rich elemental diet for 12 weeks. Dynamic changes in immune cells, including neutrophils, monocytes, T cells and B cells, were detected by flow cytometry. Plasma cytokines were evaluated by ELISA. RESULTS: Twenty adult patients with CD were enrolled. Among them, 1 discontinued treatment due to poor compliance, and 19 patients were included for final analysis. Clinical remission was achieved in 47.37% (9/19), 63.16% (12/19), and 73.68% (14/19) patients at weeks 4, 8, and 12, respectively. Endoscopic remission and transmural healing were achieved in 52.63% (10/19) and 15.79% (3/19) patients at week 12. Notably, there was no significant difference in clinical remission between week 4 and week 8 (p = 0.33) or week 12 (p = 0.09). Furthermore, we observed a rapid reconstitution of immunologic homeostasis as early as week 4. At week 4, both the frequency and activation of neutrophils and monocytes were decreased after EEN therapy. Significant decreases in Th17 cells and naïve B cells, increases in memory B cells, and regulatory B cells were also detected. These changes remained stable at weeks 8 and 12. CONCLUSIONS: EEN with an amino-acid-rich elemental diet orchestrated immunological balances and induces clinical remission in adult CD patients as early as week 4, suggesting a 4-week EEN therapy may be feasible and practicable in clinical practice.

Malignant growth of arsenic-transformed cells depends on activated Akt induced by reactive oxygen species.

Arsenic is an identified carcinogen for humans.In this study, chronic exposure of human hepatocyte L-02 to low-doses of inorganic arsenic caused cell malignant proliferation. Meanwhile, compared with normal L-02 cells, arsenic-transformed malignant cells, L-02-As displayed more ROS and significantly higher Cyclin D1 expression as well as aerobic glycolysis. Moreover, Akt activation is followed by the upregulation of Cyclin D1 and HK2 expression in L-02-As cells, since inhibition of Akt activity by Ly294002 attenuated the colony formation in soft agar and decreased the levels of Cyclin D1 and HK2. In addition, scavenging of ROS by NAC resulted in a decreased expression of phospho-Akt, HK2 and Cyclin D1, and attenuates the ability of anchorage-independent growth ofL-02-As cells, suggested that ROS mediated the Akt activation in L-02-As cells. In summary, our results demonstrated that ROS contributes to the malignant phenotype of arsenic-transformed human hepatocyte L-02-As via the activation of Akt pathway.

Systematic review with meta-analysis: loss of response and requirement of ustekinumab dose escalation in inflammatory bowel diseases.

BACKGROUND: Ustekinumab is effective in treating Crohn's disease (CD) and ulcerative colitis (UC). However, the loss of response (LOR) to ustekinumab and the efficacy of dose escalation have not been systematically explored. METHODS: Databases were searched for eligible studies from inception through July 2021. Summary estimates were pooled, and subgroup analyses were performed to explore heterogeneity. RESULTS: We included 14 studies (CD: 13; UC: 1). In CD patients, the annual risk of LOR to ustekinumab and dose escalation among primary responders was 21% (95% confidence interval [CI] 12-31%, 1530 person-years, n = 9) per person-year and 25% (95% CI 12-32%, 657 person-years, n = 5) per person-year respectively. Clinical response was regained in 58% (95% CI 49-67%, 279 patients, n = 8) of secondary non-responders after dose escalation (interval reduction or intravenous reinduction). In UC patients, no studies provided data on LOR, but only one study showed that 35% (100/284) of patients underwent dose escalation (or sham dose adjustment), leading to an annual risk of dose escalation of 18% per person-year. After dose escalation, 58% (14/24) of the patients regained symptomatic remission. CONCLUSIONS: Primary responders with CD experienced LOR to ustekinumab at a risk of 21% per person-year and required dose escalation at a risk of 25% per person-year. Fifty-eight per cent of secondary non-responders with CD may benefit from dose escalation. LOR has not been well characterized in patients with UC.

RNF213 rare variants and cerebral arteriovenous malformation in a Chinese population.

OBJECTIVE: Cerebral arteriovenous malformation (AVM) is characterised by an abnormal tangle of arteries and veins, the rupture of which is a significant portion of the morbidity and mortality cases, especially in young populations. However, the exact risk factors and pathophysiologic mechanisms of AVM remain poorly understood. RNF213 variants have been identified as obvious susceptible factors of several cerebrovascular disorders, such as Moyamoya disease and intracranial aneurysms. Thus, this study aimed to determine whether there is an association between RNF213 rare variants and AVM. METHODS: The AVM group included 22 patients with AVM. The control group included 1007 samples from the GeneSky in-house database and 208 samples from the 1000 Genome Project of Chinese Han Population. Genomic DNA samples were extracted from the peripheral blood of the AVM patients, and targeted exome sequencing of RNF213 was performed to assess the existence of low-frequency or rare variants. Sanger sequencing was performed to validate the identified variants. Logistic regression analysis was performed to calculate the odds ratios (ORs) and 95 % confidence intervals (CIs) of the candidate variants and risk of AVM. Statistical analyses were performed using SPSS version 21.0. RESULTS: The RNF213 c.10997T>C variant (amino acid mutation p.M3666T, NM_001256071) was observed in two AVM patients after filtration. It was significantly associated with AVM in the Chinese population (ORs, 10.30 and 25.08; 95 %; CIs, 1.38-77.10 and 4.34-144.90 compared with 1000 Genome Project of Chinese Han Population and GeneSky in-house database, respectively). CONCLUSION: Rare variants of RNF213 are associated with AVM in the Chinese population, suggesting the important role of RNF213 in AVM. Further studies are needed to verify these findings.

A Cervical Histopathology Dataset for Computer Aided Diagnosis of Precancerous Lesions.

Cervical cancer, as one of the most frequently diagnosed cancers worldwide, is curable when detected early. Histopathology images play an important role in precision medicine of the cervical lesions. However, few computer aided algorithms have been explored on cervical histopathology images due to the lack of public datasets. In this article, we release a new cervical histopathology image dataset for automated precancerous diagnosis. Specifically, 100 slides from 71 patients are annotated by three independent pathologists. To show the difficulty of the task, benchmarks are obtained through both fully and weakly supervised learning. Extensive experiments based on typical classification and semantic segmentation networks are carried out to provide strong baselines. In particular, a strategy of assembling classification, segmentation, and pseudo-labeling is proposed to further improve the performance. The Dice coefficient reaches 0.7833, indicating the feasibility of computer aided diagnosis and the effectiveness of our weakly supervised ensemble algorithm. The dataset and evaluation codes are publicly available. To the best of our knowledge, it is the first public cervical histopathology dataset for automated precancerous segmentation. We believe that this work will attract researchers to explore novel algorithms on cervical automated diagnosis, thereby assisting doctors and patients clinically.

Associations between Inflammatory Cytokine Gene Polymorphisms and Susceptibilities to Intracranial Aneurysm in Chinese Population.

Intracranial aneurysm (IA) is a complex disease caused by genetic and environmental factors. Evidence indicates that inflammation plays an important role in IA occurrence. We aimed to explore the associations between inflammatory cytokine gene polymorphisms and IA in a Chinese population. This study enrolled 768 participants of Han ethnicity, including 384 patients with IA and 384 healthy individuals. Sixteen single nucleotide polymorphisms (SNPs) of IL1, IL6, IL12, and TNF-α genes were genotyped using the Sequenom MassARRAY platform. Univariate and multivariate logistic regression analyses were used to analyze the associations. We found IL12B rs3181216 was significantly associated with IA in the recessive and additive models (OR = 0.46, 95% CI = 0.23-0.89, P = 0.022; OR = 0.74, 95% CI = 0.56-0.98, P = 0.034, respectively). TNF-α rs1799964 was associated with IA in dominant and additive models (OR = 0.67, 95% CI = 0.46-0.98, P = 0.041; OR = 0.71, 95% CI = 0.51-0.98, P = 0.034, respectively). IL1A rs17561 was associated with single IA susceptibility (dominant model: OR = 0.52, 95% CI = 0.31-0.85, P = 0.040). The IL12B rs3181216 polymorphism was associated with single IA susceptibility in the recessive model (OR = 0.41, 95% CI = 0.18-0.93, P = 0.033). The IL12B rs2195940 polymorphism was associated with multiple IAs susceptibility (dominant model: OR = 0.28, 95% CI = 0.09-0.89, P = 0.031; additive model: OR = 0.28, 95% CI = 0.09-0.90, P = 0.032). TNF-α rs1799964 was associated with multiple IAs susceptibility in the dominant model (OR = 0.54, 95% CI = 0.30-0.97, P = 0.040). No associations were found between other polymorphisms and IA susceptibility. Therefore, IL1A, IL12B, and TNF-α gene polymorphisms are associated with IA susceptibility in a Chinese population.

Comparison between tension band and cerclage with X-Plate and lag screws in treatment of comminuted patellar fractures.

BACKGROUND: Comminuted patellar fractures are not rare, and the ideal treatment method remains controversial. The present study was conducted to evaluate effects and compare complications of two different methods used to treat comminuted patellar fractures. METHODS: From March 2010 to August 2016, 102 cases of 34-C2 or 34-C3 comminuted patellar fractures were treated at our hospital, wherein patients received two different treatments: titanium cable tension band with cerclage method (group A) and intrafragmentary screws with X-shaped plating technique (group B). At follow-ups, articular step-off, range of motion (ROM), Lysholm scores, time of union, and complications were recorded and analyzed. Radiographic and clinical data as well as rate of complications were statistically analyzed. RESULTS: In total, 87 patients were included in the final analysis (n = 47 in group A and n = 40 in group B). No significant differences were noted in terms of cost of implant, age, gender, rate of 34-C3 fractures, rate of layered inferior pole fractures, postoperative articular step-off and union time. At 2-year follow-up, average Lysholm scores, ROM and rate of complications were (89.0 ± 4.5), (122°±12°) and (27.7%) in group A and (90.2 ± 3.9), (124°±11°) and (17.5%) in group B, respectively, with no significant differences (p > 0.05). The mean time of surgery in group B was shorter than that in group A with significant difference (p < 0.05). CONCLUSIONS: Treatment using the intrafragmentary screws and plate method for amenable comminuted patellar fractures achieved similar complication rate and favorable functional outcomes at the 2-year follow-up, which was comparable to the titanium cable tension band with cerclage method. Thus, the intrafragmentary screws and plate method is effective, safe and convenient for 34-C2/C3 comminuted patellar fractures, especially appropriate for patients with layered fragments.

Triple Up-Sampling Segmentation Network With Distribution Consistency Loss for Pathological Diagnosis of Cervical Precancerous Lesions.

OBJECTIVE: Cervical cancer, as one of the most frequently diagnosed cancers in women, is curable when detected early. However, automated algorithms for cervical pathology precancerous diagnosis are limited. METHODS: In this paper, instead of popular patch-wise classification, an end-to-end patch-wise segmentation algorithm is proposed to focus on the spatial structure changes of pathological tissues. Specifically, a triple up-sampling segmentation network (TriUpSegNet) is constructed to aggregate spatial information. Second, a distribution consistency loss (DC-loss) is designed to constrain the model to fit the inter-class relationship of the cervix. Third, the Gauss-like weighted post-processing is employed to reduce patch stitching deviation and noise. RESULTS: The algorithm is evaluated on three challenging and public datasets: 1) MTCHI for cervical precancerous diagnosis, 2) DigestPath for colon cancer, and 3) PAIP for liver cancer. The Dice coefficient is 0.7413 on the MTCHI dataset, which is significantly higher than the published state-of-the-art results. CONCLUSION: Experiments on the public dataset MTCHI indicate the superiority of the proposed algorithm on cervical pathology precancerous diagnosis. In addition, the experiments on two other pathological datasets, i.e., DigestPath and PAIP, demonstrate the effectiveness and generalization ability of the TriUpSegNet and weighted post-processing on colon and liver cancers. SIGNIFICANCE: The end-to-end TriUpSegNet with DC-loss and weighted post-processing leads to improved segmentation in pathology of various cancers.

Targeting long non-coding RNA MALAT1 alleviates retinal neurodegeneration in diabetic mice.

AIM: To observe the effect of inhibiting long non-coding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) on diabetic neurodegeneration. METHODS: Thirty-six 8-week-old C57BL/6 mice were randomly divided into normal control, diabetic control, diabetic scrambled small interfering RNAs (siRNAs) and diabetic MALAT1-siRNA groups. After diabetic induction with streptozocin intraperitoneally-injection, the diabetic MALAT1-siRNA group was intravitreally injected with 1 µL 20 µmol/L MALAT1 siRNA, and the diabetic scrambled siRNA group was injected with the same amount of scrambled siRNA. Electroretinography was performed to examine photoreceptor functions 16wk after diabetes induction. MALAT1 expression was detected via real time polymerase chain reaction. Cone morphological changes were examined using immunofluorescence. Rod morphological changes were examined by determining outer nuclear layer (ONL) thickness. RESULTS: The upregulation of retinal MALAT1 expression was detected in the diabetic control mice, while MALAT1 expression in the diabetic MALAT1-siRNA mice was decreased by 91.48% compared to diabetic control mice. The diabetic MALAT1-siRNA and diabetic control mice showed lower a-wave and b-wave amplitudes than did the normal control mice in scotopic and photopic electroretinogram, while the diabetic MALAT1-siRNA mice showed higher amplitudes than diabetic control mice. Morphological examination revealed that ONL thickness in the diabetic MALAT1-siRNA and diabetic control mice was lower than normal control mice. However, ONL thickness was greater in the diabetic MALAT1-siRNA mice than diabetic control mice. Moreover, the diabetic control mice performed a sparser cone cell arrangement and shorter outer segment morphology than diabetic MALAT1-siRNA mice. CONCLUSION: Inhibiting retinal MALAT1 results in mitigative effects on the retinal photoreceptors, thus alleviating diabetic neurodegeneration.

Rare RNF213 variants and the risk of intracranial artery stenosis/occlusion disease in Chinese population: a case-control study.

BACKGROUND: RNF213 rare variant-p.R4810K (rs112735431) was significantly associated with intracranial artery stenosis/occlusion disease (ICASO) in Japan and Korea and to a lesser degree in China. Considering the allelic heterogeneity, we performed target exome sequencing of RNF213 with the aim to identify the rare variants spectrum and their association with ICASO in a Chinese population and further to explore whether the rare variants carrier patients present specific clinical phenotype. METHODS: Target exome sequencing of RNF213 was performed in 250 ICASO patients using FastTarget sequencing technology. Various filtering process were used to select the candidate variants. Control individuals were obtain from 1000 Genome Project (208 Chinese samples) and GeneSky in-house database (1007 samples). Gene-based association analyses were conducted to identify the association between RNF213 rare variants and ICASO. The clinical characteristics of rare variant carriers and non-carriers were compared using Chi-squared test or Fisher's exact test. RESULTS: After filtration, 18 rare variants were identified in 39 patients. Gene-based association test showed that rare variants of RNF213 were significantly associated with ICASO (Minor allele frequency < 0.05, WSS p = 4.88 × 10- 10; SKAT p = 9.68 × 10- 6; SKAT-O p = 3.42 × 10- 9). There were no significant clinical characteristic differences other than the diagnosis age which was older in the carriers than the non-carriers (60.5 ± 6.2 vs 57.3 ± 8.9 years old, p = 0.028). CONCLUSION: Rare variants of RNF213 are associated with ICASO in Chinese. However, there are limited genetic diagnosis values of the gene due to no specific phenotypic presentation in the carriers and non carrier patients.

Comparison of the Use of Vonoprazan and Proton Pump Inhibitors for the Treatment of Peptic Ulcers Resulting from Endoscopic Submucosal Dissection: A Systematic Review and Meta-Analysis.

BACKGROUND Currently, proton pump inhibitors (PPIs) are the first-line treatment for ulcers resulting from endoscopic submucosal dissection (ESD). Vonoprazan is a new oral potassium-competitive acid blocker (P-CAB). The aim of this systematic review and meta-analysis was to compare the efficacy, safety, and tolerance of vonoprazan with PPIs in the treatment of peptic ulcers resulting from ESD. MATERIAL AND METHODS Published results of randomized clinical trials (RCTs) comparing vonoprazan with PPIs in the treatment of ulcers resulting from ESD were identified up to March 2018. The main clinical endpoints evaluated were healing rate and adverse events. The meta-analysis included quality assessment of the studies, statistical analysis of endpoints, and sensitivity analysis using Revman version 5.3 meta-analysis software. RESULTS Systematic literature review identified seven published studies that included 548 patients. Five studies were published as full-text manuscripts, and two studies were published as abstracts. Meta-analysis of the vonoprazan treatment, compared with PPI treatment, for ESD showed that the pooled relative risk (RR) of healing rate was 0.64 (95% CI, 0.33-1.22) for the 4-week study group and 0.98 (95% CI, 0.84-1.15) for the 8-week study group. The RR for adverse events was 0.65 (95% CI, 0.31-1.38) (P>0.05). No statistical evidence of publication bias was found. CONCLUSIONS The findings of the systematic review and meta-analysis showed that the efficacy of vonoprazan was comparable with PPIs for the treatment of peptic ulcers following ESD. Further studies are required to support the safety and efficacy of vonoprazan compared with different types of PPIs.

Bioinformatics Analysis of Weighted Genes in Diabetic Retinopathy.

Purpose: Intricate signaling networks and transcriptional regulators translate pathogen recognition into defense responses. The aim of this study was to identify the weighted genes involved in diabetic retinopathy (DR) in different rodent models of diabetes. Methods: We performed a gene coexpression analysis of publicly available microarray data, namely, the GSE19122 dataset from the Gene Expression Omnibus database. We conducted gene coexpression analysis on the microarray data to identify modules of functionally related coexpressed genes that are differentially expressed in different rodent models. We leveraged a richly curated expression dataset and used weighted gene coexpression network analysis to construct an undirected network. We screened 30 genes in the most closely related module. A protein-protein interaction network was constructed for the genes in the most related module using the Search Tool for the Retrieval of Interacting Genes. Gene Ontology enrichment analysis and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis were performed for the 30 genes. Results: Five visual perception-related genes (Pde6g, Guca1a, Rho, Sag, and Prph2) were significantly upregulated. Based on the competing endogenous RNA hypothesis, a link between the long noncoding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) and visual perception-related mRNAs was constructed using bioinformatics tools. Six potential microRNAs (miR-155-5p, miR-1a-3p, miR-122-5p, miR-223-3p, miR-125b-5p, and miR-124-3p) were also screened. Conclusions: MALAT1 might play important roles in DR by regulating Sag and Guca1a through miR-124-3p and regulating Pde6g through miR-125b-5p.

USP22 drives colorectal cancer invasion and metastasis via epithelial-mesenchymal transition by activating AP4.

Ubiquitin specific peptidase 22 (USP22), a putative cancer stem cell marker, is overexpressed in liver metastases of colorectal cancer (CRC). However, the mechanism by which USP22 promotes CRC metastasis remains largely unknown. Here, we report that USP22 and AP4 are simultaneously overexpressed during TGF-ß1-induced CRC cell epithelial-mesenchymal transition (EMT). USP22 up-regulation enhances CRC cell migration and invasion and EMT-related marker and AP4 expression, but these effects are partly blocked by AP4 knockdown. In addition, USP22 binds to the promoter region of AP4 to activate its transcription. In vivo, elevated USP22 expression promotes CRC cell metastasis to the lungs in nude mice, as evidenced by the fact that CRC metastatic nodules stain deeply positive for USP22 and AP4. In human CRC tissues, the genes encoding USP22 and AP4 are overexpressed in metastatic liver lesions compared with primary cancer tissues, and their overexpression is significantly associated with poor CRC patient survival. These findings indicate that USP22 and AP4 may serve as prognostic markers for predicting the risk of developing distant metastases in CRC.

Poly[diaqua[mu-1,4-bis(imidazol-1-ylmethyl)benzene-kappa2N3:N3'](mu-trans-cyclohexane-1,4-carboxylato-kappa2O1:O4)manganese(II)]: a three-dimensional hydrogen-bonding alpha-polonium net.

In the title coordination compound, [Mn(C8H10O4)(C14H14N4)(H2O)2]n, each Mn(II) centre occupies an inversion centre. The 1,4-bis(imidazol-1-ylmethyl)benzene (1,4-bix) ligand and the trans-cyclohexane-1,4-dicarboxylate dianion (chdc) both function in bridging modes, linking adjacent Mn(II) centres into a two-dimensional four-connected (4,4) network. These two-dimensional layers are stacked in a parallel mode. Hydrogen bonds between water molecules and carboxylate O atoms link neighbouring (4,4) networks, yielding a three-dimensional alpha-polonium net.