Endoscopic Submucosal Dissection Criteria for Differentiated-type Early Gastric Cancer Are Applicable to Mixed-type Differentiated Predominant.

BACKGROUND: There is a lack of sufficient evidence on whether mixed-type differentiated predominant early gastric cancer (MD-EGC) can be treated endoscopically by referring to the criteria for differentiated-type early gastric cancer (EGC). This study aims to evaluate the efficacy of endoscopic submucosal dissection (ESD) in MD-EGC. METHODS: Patients with differentiated-type EGC treated with ESD first from January 2015 to June 2021 were reviewed, including MD-EGC and pure differentiated-type EGC (PD-EGC). Clinical data, including the clinicopathological characteristics, resection outcomes of ESD, and recurrence and survival time, were collected, and the difference between MD-EGC and PD-EGC was tested. RESULTS: A total of 48 patients (48 lesions) with MD-EGC and 850 patients (890 lesions) with PD-EGC were included. Compared with PD-EGC, MD-EGC had a higher submucosal invasion rate (37.5% vs. 13.7%, P<0.001) and lymphatic invasion rate (10.4% vs. 0.4%, P<0.001). The rates of complete resection (70.8% vs. 92.5%, P<0.001) and curative resection (54.2% vs. 87.4%, P<0.001) in MD-EGC were lower than those of PD-EGC. Multivariate analysis revealed that MD-EGC (OR 4.26, 95% CI, 2.22-8.17, P<0.001) was an independent risk factor for noncurative resection. However, when curative resection was achieved, there was no significant difference in the rates of recurrence (P=0.424) between the 2 groups, whether local or metachronous recurrence. Similarly, the rates of survival(P=0.168) were no significant difference. CONCLUSIONS: Despite the greater malignancy and lower endoscopic curative resection rate of MD-EGC, patients who met curative resection had a favorable long-term prognosis.

Identification of hub genes associated with Helicobacter pylori infection and type 2 diabetes mellitus: A pilot bioinformatics study.

BACKGROUND: Helicobacter pylori (H. pylori) infection is related to various extragastric diseases including type 2 diabetes mellitus (T2DM). However, the possible mechanisms connecting H. pylori infection and T2DM remain unknown. AIM: To explore potential molecular connections between H. pylori infection and T2DM. METHODS: We extracted gene expression arrays from three online datasets (GSE60427, GSE27411 and GSE115601). Differentially expressed genes (DEGs) commonly present in patients with H. pylori infection and T2DM were identified. Hub genes were validated using human gastric biopsy samples. Correlations between hub genes and immune cell infiltration, miRNAs, and transcription factors (TFs) were further analyzed. RESULTS: A total of 67 DEGs were commonly presented in patients with H. pylori infection and T2DM. Five significantly upregulated hub genes, including TLR4, ITGAM, C5AR1, FCER1G, and FCGR2A, were finally identified, all of which are closely related to immune cell infiltration. The gene-miRNA analysis detected 13 miRNAs with at least two gene cross-links. TF-gene interaction networks showed that TLR4 was coregulated by 26 TFs, the largest number of TFs among the 5 hub genes. CONCLUSION: We identified five hub genes that may have molecular connections between H. pylori infection and T2DM. This study provides new insights into the pathogenesis of H. pylori-induced onset of T2DM.

Effectiveness and safety of Moluodan in the treatment of precancerous lesions of gastric cancer: A randomized clinical trial.

OBJECTIVE: To investigate the clinical potential and safety of Moluodan to reverse gastric precancerous lesions. METHODS: Patients aged 18-70 years diagnosed with moderate-to-severe atrophy and/or moderate-to-severe intestinal metaplasia, with or without low-grade dysplasia, and negative for Helicobacter pylori were recruited in this randomized, double-blind, parallel-controlled trial. The primary outcome was the improvement of global histological diagnosis at 1-year follow-up endoscopy using the operative link for gastritis assessment, the operative link for gastric intestinal metaplasia assessment, and the disappearance rate of dysplasia. RESULTS: Between November 3, 2017 and January 27, 2021, 166 subjects were randomly assigned to the Moluodan group, 168 to the folic acid group, 84 to the combination group, and 84 to the high-dose Moluodan group. The improvement in global histological diagnosis was achieved in 60 (39.5%) subjects receiving Moluodan, 59 (37.8%) receiving folic acid, 26 (32.1%) receiving the combined drugs, and 36 (47.4%) receiving high-dose Moluodan. Moluodan was non-inferior to folic acid (95% confidence interval: -9.2 to 12.5; P = 0.02). High-dose Moluodan had a trend for better protective efficacy, though there was no statistical significance. The disappearance rate of dysplasia was 82.8% in the Moluodan group, which was superior to folic acid (53.9%; P = 0.006). No drug-related serious adverse events were observed. CONCLUSIONS: One pack of Moluodan three times daily for 1 year was safe and effective in reversing gastric precancerous lesions, especially dysplasia. Doubling its dose showed a better efficacy trend.

Prognostic model of hepatocellular carcinoma based on cancer grade.

BACKGROUND: Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. With highly invasive biological characteristics and a lack of obvious clinical manifestations, HCC usually has a poor prognosis and ranks fourth in cancer mortality. The aetiology and exact molecular mechanism of primary HCC are still unclear. AIM: To select the characteristic genes that are significantly associated with the prognosis of HCC patients and construct a prognosis model of this malignancy. METHODS: By comparing the gene expression levels of patients with different cancer grades of HCC, we screened out differentially expressed genes associated with tumour grade. By protein-protein interaction (PPI) network analysis, we obtained the top 2 PPI networks and hub genes from these differentially expressed genes. By using least absolute shrinkage and selection operator Cox regression, 13 prognostic genes were selected for feature extraction, and a prognostic risk model of HCC was established. RESULTS: The model had significant prognostic ability in HCC. We also analysed the biological functions of these prognostic genes. CONCLUSION: By comparing the gene profiles of patients with different stages of HCC, We have constructed a prognosis model consisting of 13 genes that have important prognostic value. This model has good application value and can be explained clinically.

Prediction of lymph node metastasis in early gastric signet-ring cell carcinoma: A real-world retrospective cohort study.

BACKGROUND: Signet-ring cell carcinoma (SRCC) was previously thought to have a worse prognosis than other differentiated gastric cancer (GC), however, recent studies have shown that the prognosis of SRCC is related to pathological type. We hypothesize that patients with SRCC and with different SRCC pathological components have different probability of lymph node metastasis (LNM). AIM: To establish models to predict LNM in early GC (EGC), including early gastric SRCC. METHODS: Clinical data from EGC patients who had undergone gastrectomy at the First Affiliated Hospital of Nanjing Medical University from January 2012 to March 2022 were reviewed. The patients were divided into three groups based on type: Pure SRCC, mixed SRCC, and non-signet ring cell carcinoma (NSRC). The risk factors were identified through statistical tests using SPSS 23.0, R, and Em-powerStats software. RESULTS: A total of 1922 subjects with EGC were enrolled in this study, and included 249 SRCC patients and 1673 NSRC patients, while 278 of the patients (14.46%) presented with LNM. Multivariable analysis showed that gender, tumor size, depth of invasion, lymphovascular invasion, ulceration, and histological subtype were independent risk factors for LNM in EGC. Establishment and analysis using prediction models of EGC showed that the artificial neural network model was better than the logistic regression model in terms of sensitivity and accuracy (98.0% vs 58.1%, P = 0.034; 88.4% vs 86.8%, P < 0.001, respectively). Among the 249 SRCC patients, LNM was more common in mixed (35.06%) rather than in pure SRCC (8.42%, P < 0.001). The area under the ROC curve of the logistic regression model for LNM in SRCC was 0.760 (95%CI: 0.682-0.843), while the area under the operating characteristic curve of the internal validation set was 0.734 (95%CI: 0.643-0.826). The subgroups analysis of pure types showed that LNM was more common in patients with a tumor size > 2 cm (OR = 5.422, P = 0.038). CONCLUSION: A validated prediction model was developed to recognize the risk of LNM in EGC and early gastric SRCC, which can aid in pre-surgical decision making of the best method of treatment for patients.

A Prediction Model Based on the Risk Factors Associated with Pathological Upgrading in Patients with Early-Stage Gastric Neoplasms Diagnosed by Endoscopic Forceps Biopsy.

Background/Aims: The discrepancies between the diagnosis of preoperative endoscopic forceps biopsy (EFB) and endoscopic submucosal dissection (ESD) in patients with early gastric neoplasm (EGN) exist objectively. Among them, pathological upgrading directly influences the accuracy and appropriateness of clinical decisions. The aims of this study were to investigate the risk factors for the discrepancies, with a particular focus on pathological upgrading and to establish a prediction model for estimating the risk of pathological upgrading after EFB. Methods: We retrospectively collected the records of 978 patients who underwent ESD from December 1, 2017 to July 31, 2021 and who had a final histopathology determination of EGN. A nomogram to predict the risk of pathological upgrading was constructed after analyzing subgroup differences among the 901 lesions enrolled. Results: The ratio of pathological upgrading was 510 of 953 (53.5%). Clinical, laboratorial and endoscopic characteristics were analyzed using univariable and binary multivariable logistic regression analyses. A nomogram was constructed by including age, history of chronic atrophic gastritis, symptoms of digestive system, blood high density lipoprotein concentration, macroscopic type, pathological diagnosis of EFB, uneven surface, remarkable redness, and lesion size. The C-statistics were 0.804 (95% confidence interval, 0.774 to 0.834) and 0.748 (95% confidence interval, 0.664 to 0.832) in the training and validation set, respectively. We also built an online webserver based on the proposed nomogram for convenient clinical use. Conclusions: The clinical value of identifying the preoperative diagnosis of EGN lesions is limited when using EFB separately. We have developed a nomogram that can predict the probability of pathological upgrading with good calibration and discrimination value.

Endoscopic detection of esophageal low-grade squamous dysplasia: How to predict pathologic upgrades before treatment?

OBJECTIVE: In this study we aimed to predict the risk factors related to histopathologic upgrade after endoscopic submucosal dissection (ESD) in patients with pre-ESD esophageal squamous low-grade intraepithelial neoplasm (LGIN). METHODS: A training cohort of 201 patients with biopsy-confirmed esophageal squamous LGIN and underwent ESD at a tertiary medical center between January 2017 and July 2019 were included. Risk factors for histological upgrade were identified using the least absolute shrinkage and selection operator (LASSO) regression. A nomogram was then established. Internal validation was evaluated by discrimination, calibration plot, and decision-curve analysis. Another cohort of 48 patients were prospectively collected from July 2019 to June 2021 for external validation of the nomogram. RESULTS: The rate of histological upgrade was 34.8% (70/201) and 27.1% (13/48) in the training and validation sets, respectively. LASSO regression identified that tumor area (mm2 ) per biopsy, Lugol's staining pattern, background coloration, and the circumferential range of the lesion were significantly associated with histological upgrade. The final nomogram attained favorable prediction efficacy in the training cohort (area under the receiver operating curve [AUROC] 0.96, 95% confidence interval [CI] 0.94-0.98) and validation cohort (AUROC 0.92, 95% CI 0.79 -0.99). This model generated well-fitted calibration and clinical-decision curves in both cohorts. CONCLUSIONS: The nomogram may better guide clinical decision on whether performing EDS or follow-up for suspicious lesions in patients with biopsy-confirmed esophageal squamous LGIN.

Chinese Consensus Report on Family-Based Helicobacter pylori Infection Control and Management (2021 Edition).

OBJECTIVE: Helicobacter pylori infection is mostly a family-based infectious disease. To facilitate its prevention and management, a national consensus meeting was held to review current evidence and propose strategies for population-wide and family-based H. pylori infection control and management to reduce the related disease burden. METHODS: Fifty-seven experts from 41 major universities and institutions in 20 provinces/regions of mainland China were invited to review evidence and modify statements using Delphi process and grading of recommendations assessment, development and evaluation system. The consensus level was defined as ≥80% for agreement on the proposed statements. RESULTS: Experts discussed and modified the original 23 statements on family-based H. pylori infection transmission, control and management, and reached consensus on 16 statements. The final report consists of three parts: (1) H. pylori infection and transmission among family members, (2) prevention and management of H. pylori infection in children and elderly people within households, and (3) strategies for prevention and management of H. pylori infection for family members. In addition to the 'test-and-treat' and 'screen-and-treat' strategies, this consensus also introduced a novel third 'family-based H. pylori infection control and management' strategy to prevent its intrafamilial transmission and development of related diseases. CONCLUSION: H. pylori is transmissible from person to person, and among family members. A family-based H. pylori prevention and eradication strategy would be a suitable approach to prevent its intra-familial transmission and related diseases. The notion and practice would be beneficial not only for Chinese residents but also valuable as a reference for other highly infected areas.

New genotypes of Helicobacter Pylori VacA d-region identified from global strains.

BACKGROUND: Pathogenesis of Helicobacter Pylori (HP) vacuolating toxin A (vacA) depends on polymorphic diversity within the signal (s), middle (m), intermediate (i), deletion (d) and c-regions. These regions show distinct allelic diversity. The s-region, m-region and the c-region (a 15 bp deletion at the 3'-end region of the p55 domain of the vacA gene) exist as 2 types (s1, s2, m1, m2, c1 and c2), while the i-region has 3 allelic types (i1, i2 and i3). The locus of d-region of the vacA gene has also been classified into 2 genotypes, namely d1 and d2. We investigated the "d-region"/"loop region" through bioinformatics, to predict its properties and relation to disease. One thousand two hundred fifty-nine strains from the NCBI nucleotide database and the dryad database with complete vacA sequences were included in the study. The sequences were aligned using BioEdit and analyzed using Lasergene and BLAST. The secondary structure and physicochemical properties of the region were predicted using PredictProtein. RESULTS: We identified 31 highly polymorphic genotypes in the "d-region", with a mean length of 34 amino acids (9 ~ 55 amino acids). We further classified the 31 genotypes into 3 main types, namely K-type (strains starting with the KDKP motif in the "d-region"), Q-type (strains starting with the KNQT motif), and E-type (strains starting with the ESKT motif) respectively. The most common type, K-type, is more prevalent in cancer patients (80.87%) and is associated with the s1i1m1c1 genotypes (P < .01). Incidentally, a new region expressing sequence diversity (2 aa deletion) at the C-terminus of the p55 domain of vacA was identified during bioinformatics analysis. CONCLUSIONS: Prediction of secondary structures shows that the "d-region" adopts a loop conformation and is a disordered region.

Anti-inflammatory and analgesic activities of indigo through regulating the IKKß/IκB/NF-κB pathway in mice.

This study investigated the anti-inflammatory and analgesic activities of indigo in mice and explored the possible related mechanisms. Xylene-induced ear edema, carrageenan-induced paw edema, and acetic acid-induced vascular permeability tests were used in investigating the anti-inflammatory activities. The anti-nociceptive effects of indigo were assessed through acetic acid-induced writhing, hot plate test, and formalin test, and spontaneous locomotor activity and motor performance were evaluated. The mechanisms of activities of indigo were explored by evaluating the expression levels of IκB kinase (IKK)ß, p-IKKß, inhibitor κB (IκB)α, p-IκBα, p65 nuclear factor (NF)-kB, p-p65 NF-κB, cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS) through western blotting and the expression levels of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and prostaglandin E2 (PGE2) through enzyme-linked immunosorbent assay. The results showed that indigo significantly reduced xylene-induced ear edema, carrageenan-induced paw edema, and acetic acid-induced vascular permeation. In addition, indigo significantly inhibited nociception induced by acetic acid and formalin. However, the level of nociception was not decreased by indigo in the hot plate test, and indigo did not affect spontaneous locomotor activity and motor performance. The expression levels of p-IKKß, p-IκBα, p65 NF-kB, p-p65 NF-κB, COX-2, iNOS, TNF-α, IL-1ß, IL-6, and PGE2 decreased, whereas the expression level of IκBα increased obviously after indigo treatment. In conclusion, indigo exerts significant anti-inflammatory and analgesic activities in mice by inhibiting IKKß phosphorylation and reducing the production of important pain mediators, such as PGE2 and COX-2, via the IKKß/IκB/NF-κB pathway.

A Comparison by Meta-Analysis of Papillary Early Gastric Carcinoma to Its Tubular Counterpart for the Risk of Lymph Node Metastasis and Submucosal Invasion.

BACKGROUND AND AIM: At present, the decision to perform endoscopic resection for treating either papillary early gastric cancer (EGC) or tubular EGC is made according to identical criteria. However, there is controversy in the literature whether the risk of lymph node metastasis (LNM) and submucosal invasion for both disease modalities is equal, and this prompts investigation to clarify this issue. METHODS: The PubMed and Web of Science databases were searched for relevant studies published up to January 2017. Data were extracted, and the pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated using a random-effects or a fixed-effects model, according to heterogeneity. RESULTS: A total of 13 studies were included in this analysis. Papillary EGC had a significantly higher LNM risk (OR, 1.97; 95% CI, 1.38-2.82) and submucosal invasion risk (OR, 1.44; 95% CI, 1.08-1.93), compared with tubular EGC. Stratified by geographic location, a significantly increased risk of LNM (OR, 2.28; 95% CI, 1.57-3.30) and submucosal invasion (OR, 1.52; 95% CI, 1.13-2.04) associated with papillary EGC was found in Asian studies. In addition, papillary EGC exhibited significantly more frequent elevated/flat growth patterns (OR, 7.54, 95% CI, 4.76-11.96). CONCLUSIONS: Our study identifies an increased risk for submucosal invasion and LNM in papillary EGC compared with tubular EGC, indicating that papillary EGC requires more careful clinical management compared with tubular EGC.

Synthesis, crystal structure and antiproliferative mechanisms of 2-acetylpyridine-thiosemicarbazones Ga(III) with a greater selectivity against tumor cells.

Thiosemicarbazone Ga(III) complexes (C3-C5) were synthesized and characterized by X-ray single crystal diffraction, and they were all 1:1 ligand/Ga(III) complexes. The antiproliferative activity of these Ga(III) complexes was tested against three cancer cell lines, demonstrating that Ga(III) complexes showed about 3-10 folds more anticancer activity than their ligands alone. Importantly, thiosemicarbazones and Ga(III) complexes have a low toxicity to human fetal lung fibroblast cells (MRC-5) and exhibit a high therapeutic index for tumor cells. The results of UV-visible spectroscopy showed that the binding constant of C4 with Topo-I-DNA was significantly higher than that of L4. The Ga(III) complex (C4) caused Topo-I inhibition and distinct DNA cleavage. Moreover, Ga(III) complex and thiosemicarbazone ligand prolonged the G1 phase in NCI-H460 cell cycle, which might be depended on the ability of these compounds to affect the expression of cell cycle related proteins.

Risk factors for intestinal metaplasia in a southeastern Chinese population: an analysis of 28,745 cases.

PURPOSE: To identify risk factors for intestinal metaplasia in a southeastern Chinese population. METHODS: Subjects who underwent upper GI endoscopy and endoscopic biopsy in the First Affiliated Hospital of Nanjing Medical University from 2008 to 2013 were included into this study. Various demographic, geographic, clinical and pathological data were analyzed separately to identify risk factors for intestinal metaplasia. RESULTS: The incidence of intestinal metaplasia differed significantly in 17 municipal areas ranging from 16.79 to 38.56% and was positively correlated with the age range of 40-70 years, male gender, gastric ulcer, bile reflux, Helicobacter pylori infection, atrophic gastritis, dysplasia, gastric cancer, degree of chronic and acute inflammation, and gross domestic product per capita (P < 0.01). Multivariate linear regression analysis indicated that only gross domestic product per capita revealed a significant difference in the incidence of intestinal metaplasia among all factors mentioned. CONCLUSION: This study confirms age, male gender, gastric ulcer, bile reflux, H. pylori infection, severe degree of chronic and acute inflammation to be the risk factors for intestinal metaplasia. We speculate that the gross domestic product per capita of different areas may be a potential independent risk factor impacting the incidence of intestinal metaplasia.

Mouse Double Minute 2 Actively Suppresses p53 Activity in Oocytes during Mouse Folliculogenesis.

The p53 signaling network is indispensible in cellular stress responses and tumor suppression. Negative regulations of p53 by mouse double minute 2 (MDM2) and its homolog MDM4 are an integrated component of the network and have been implicated in regulating the stress responses and the maintenance of normal development and homeostasis of multiple somatic cell lineages. However, the regulatory role of MDM2 on p53 and stress responses in female germ cells remains undetermined. Here, we used the Cre-loxP system to delete Mdm2 in oocytes at different stages of folliculogenesis in mice. Mdm2 deletion resulted in a clear p53 nuclear accumulation in the oocytes and impeded fertilities with early follicular loss in mice, resembling human premature ovarian failure phenotypes. These phenotypes were fully rescued by concurrent deletion of p53 in mice. In addition, Nutlin-3, a small molecule compound that inhibited the binding of MDM2 to p53, also promoted p53-dependent oocyte death. Although cancer therapeutic agents 5-fluorouracil and doxorubicin could not induce a robust p53 activation in the wild-type oocytes, they induced p53 nuclear accumulation in the Mdm2 and Mdm4 double heterozygous oocytes. These results demonstrated a critical prosurvival role for MDM2 in the oocytes. Moreover, they suggested a more tightened and rigorous regulatory mode for the MDM2/MDM4-p53 network in female germ cells under stress situations.

Downward trend in the prevalence of Helicobacter pylori infections and corresponding frequent upper gastrointestinal diseases profile changes in Southeastern China between 2003 and 2012.

This present study aims to determine trends in the prevalence of H. pylori infections in Southeastern China between 2003 and 2012, and investigate corresponding changes in the prevalence of upper gastrointestinal diseases. This retrospective study screened 196,442 patients with a mean age of 47.49 ± 14.47 years (age range 5-100 years) in Southeastern China, and a total of 134,812 cases of an endoscopy-referral patient population with digestive symptoms between 2003 and 2012 were enrolled. Based on esophago-gastro-duodenoscopy and pathology, patients diagnosed with chronic gastritis, peptic ulcer, gastric cancer or reflux esophagitis were included in this study. Basic demographic and clinical characteristics such as H. pylori infection status and endoscopic findings were collected and analyzed. Among the 134,812 subjects, mean prevalence of H. pylori infection was 31.97 %; which demonstrated a linear downward trend from 42.40 to 23.82 % (P < 0.001) at an annual rate of 2 % from 2003 to 2012. Similarly, the prevalence of duodenal and gastric ulcer rapidly decreased from 12.65 to 6.57 % and from 7.51 to 3.78 %, respectively; while the prevalence of gastric cancer (from 3.76 to 2.34 %) did not significantly change in the same time period. In contrast, the prevalence of reflux esophagitis increased from 6.19 to 12.80 %. The progressively decreasing prevalence of H. pylori infections from 2003 to 2012 in Southeastern China appears to be linked with the decline of related upper gastrointestinal diseases and increase of some gastrointestinal motility diseases.

Anatomical predilection of intestinal metaplasia based on 78,335 endoscopic cases.

BACKGROUND/AIMS: Gastric intestinal metaplasia (IM) is an important risk factor for intestinal-type gastric carcinoma, and successful treatment critically depends on its timely detection. In order to guide appropriate endoscopic surveillance, objective knowledge on the anatomical predilection of intestinal metaplasia development is urgently needed. MATERIALS AND METHODS: A total of 78,335 cases who underwent gastroduodenoscopy from 2008 to 2013 in Jiangsu and Anhui provinces in China, were studied. Demographic and clinical characteristics, as well as biopsy location and histological results, were analyzed. RESULTS: This study revealed that intestinal metaplasia incidence was 28.5% in angulus, 20.24% in lesser curvature of the antrum, and 25.48% in corpus; and all these were significantly higher than those observed in other sites (P < 0.01). Histological grading of intestinal metaplasia in the lesser curvature of the antrum and angulus was generally worse than the grading observed in the greater curvature of the antrum. For Helicobacter pylori-positive patients, acute inflammation was more severe in the lesser curvature of the antrum compared with the greater curvature. In the H. Pylori-negative group, both acute and chronic inflammations were more severe in the lesser curvature of the antrum. CONCLUSIONS: The angulus, lesser curvature in the antrum, and corpus are most prone to the development of intestinal metaplasia. Inflammation is most severe in the lesser curvature of the antrum, which corresponds to a higher predilection to develop intestinal metaplasia at this site. The lesser curvature of the antrum and corpus require the most attention during endoscopic biopsy surveillance.

Induced Pluripotent Stem Cells in Huntington's Disease: Disease Modeling and the Potential for Cell-Based Therapy.

Huntington's disease (HD) is an incurable neurodegenerative disorder that is characterized by motor dysfunction, cognitive impairment, and behavioral abnormalities. It is an autosomal dominant disorder caused by a CAG repeat expansion in the huntingtin gene, resulting in progressive neuronal loss predominately in the striatum and cortex. Despite the discovery of the causative gene in 1993, the exact mechanisms underlying HD pathogenesis have yet to be elucidated. Treatments that slow or halt the disease process are currently unavailable. Recent advances in induced pluripotent stem cell (iPSC) technologies have transformed our ability to study disease in human neural cells. Here, we firstly review the progress made to model HD in vitro using patient-derived iPSCs, which reveal unique insights into illuminating molecular mechanisms and provide a novel human cell-based platform for drug discovery. We then highlight the promises and challenges for pluripotent stem cells that might be used as a therapeutic source for cell replacement therapy of the lost neurons in HD brains.

p53 in the Myeloid Lineage Modulates an Inflammatory Microenvironment Limiting Initiation and Invasion of Intestinal Tumors.

Chronic inflammation promotes the development and progression of various epithelial tumors. Wild-type p53 suppresses inflammation, but it is unclear whether the role of p53 in suppression of inflammation is linked to its tumor suppression function. Here, we established mouse models of myeloid lineage-specific p53 deletion or activation to examine its role in inflammation-related intestinal tumorigenesis. Impaired p53 in the myeloid linage resulted in elevated levels of inflammatory mediators and stimulated adenoma initiation in Apc(Min/+) mice. In contrast, mice with mild p53 activation in the myeloid lineage attenuated the inflammatory response and were more resistant to intestinal tumor development and invasion, which were initiated through Apc(Min/+) mutation or carcinogen and promoted by colitis. Furthermore, p53 activation also suppressed alternative (M2) macrophage polarization together with c-MYC downregulation. Therefore, as a regulator of macrophage function, p53 is critical to protection against tumorigenesis in a non-cell-autonomous manner.