A rare gastric lesion: diminutive, well-differentiated, Grade 3, type 3 gastric neuroendocrine tumor with extremely high ki-67 index removed en bloc under endoscopy.

Grade 3, type 3 gastric neuroendocrine tumor (g-NET) shows specific features of clinical interest and the therapeutic management of the lesion is not yet completely standardized. We present the unusual case of a 34-year-old male patient with a diminutive (less than 0.5 cm), well-differentiated, G3, type 3g-NET with extremely high Ki-67 index (higher than 80%). The lesion was subsequently removed en bloc via endoscopic submucosal dissection. Regarding the proliferation rate, Ki-67 index values usually range from 21 to 50%, and less commonly above 55%, in G3 NET. To our knowledge, this lesion represents a small size with the highest Ki-67 index diagnosed with G3 g-NET. However, as g-NET might recur even after a long duration, we recommend a long-term follow-up, such as 10 years after complete resection in patients to evaluate the endoscopic resection approach.

[Advances in serum biomarkers for early diagnosis of gastric cancer].

Early diagnosis is the key to improve the prognosis of gastric cancer. How to screen out high-risk subjects of gastric cancer in population is a hot spot. Serum-based early detection of gastric cancer is suitable for high-risk population screening, which is more convenient and safer. This article reviews the diagnostic value of serum biomarkers for gastric cancer, including serum DNA methylation, various RNAs, pepsinogen, gastrin, osteopontin, MG7-Ag and CA724. Until now, there is still lack of ideal biomarkers for gastric cancer, and searching for specific RNAs may be promising for early diagnosis and screening of gastric cancer.

Risk of gastric cancer among patients with gastric intestinal metaplasia.

Plenty of studies have assessed the association between intestinal metaplasia (IM) and gastric cancer risk, while the results were inconsistent. We aimed to assess the risk of gastric cancer among patients with IM. Systematic literature searches were conducted in PubMed, Embase and Cochrane databases. Baseline characteristics and outcomes from the included studies were extracted independently by two investigators. Either a fixed-effects or a random-effects model was used to composite the pooled OR for gastric cancer risk. Finally, a total of 21 studies, which comprised 402,636 participants and 4,535 gastric cancer patients, were finally included in the current meta-analysis. Compared with those participants without IM, IM patients were at a higher risk of gastric cancer (pooled OR = 3.58, 95% CI 2.71-4.73). We observed that incomplete IM (pooled OR = 9.48, 95% CI 4.33-20.78) but not complete IM (pooled OR = 1.55, 95% CI 0.91-2.65) was significantly associated with a higher gastric cancer risk. Besides, it appeared that gastric cancer risk was higher among patients with IM in the corpus (pooled OR = 7.39, 95% CI 4.94-11.06) than those with IM in the antrum only (pooled OR = 4.06, 95% CI 2.79-5.91). And the pooled ORs for gastric noncardia cancer and gastric cardia cancer were 4.98 (95% CI 3.12-7.95) and 1.93 (95% CI 1.15-3.24), respectively. In conclusion, patients with IM were at a higher risk of gastric cancer, especially for incomplete IM and IM in the corpus. The current evidence supports the use of IM subtypes in the surveillance of gastric cancer.

Rabeprazole mitigates obesity-induced chronic inflammation and insulin resistance associated with increased M2-type macrophage polarization.

Macrophage polarization is closely associated with obesity-induced chronic inflammation and insulin resistance. Proton pump inhibitor Rabeprazole has long been used to treat gastritis and gastric ulcers. However, whether Rabeprazole plays a role in macrophage polarization during obesity is unknown. Here, we show that Rabeprazole suppresses M1-type macrophage-mediated inflammation, leads to increased M2-type macrophages and alters the polarization status from M1 to M2 in vitro. Mechanistically, Rabe-regulated macrophage polarization is associated with inhibition of NF-κB and activation of STAT6 signaling pathways. Furthermore, Rabeprazole induces M2-type adipose tissue macrophages and alleviates chronic inflammation, improving glucose tolerance and insulin sensitivity in high-fat diet-fed mice. In addition, Rabeprazole increases CD206+ M2-type liver macrophages and relieves liver inflammation, alleviating liver injury and lipid accumulation. Thus, our findings show that Rabeprazole effectively regulates macrophage polarization and controls obesity-associated chronic inflammation and insulin resistance, thus providing a potential therapeutic strategy against obesity-associated metabolic diseases.

Proton pump inhibitors enhance macropinocytosis-mediated extracellular vesicle endocytosis by inducing membrane v-ATPase assembly.

Besides participating in diverse pathological and physiological processes, extracellular vesicles (EVs) are also excellent drug-delivery vehicles. However, clinical drugs modulating EV levels are still lacking. Here, we show that proton pump inhibitors (PPIs) reduce EVs by enhancing macropinocytosis-mediated EV uptake. PPIs accelerate intestinal cell endocytosis of autocrine immunosuppressive EVs through macropinocytosis, thereby aggravating inflammatory bowel disease. PPI-induced macropinocytosis facilitates the clearance of immunosuppressive EVs from tumour cells, improving antitumor immunity. PPI-induced macropinocytosis also increases doxorubicin and antisense oligonucleotides of microRNA-155 delivery efficiency by EVs, leading to enhanced therapeutic effects of drug-loaded EVs on tumours and acute liver failure. Mechanistically, PPIs reduce cytosolic pH, promote ATP6V1A (v-ATPase subunit) disassembly from the vacuolar membrane and enhance the assembly of plasma membrane v-ATPases, thereby inducing macropinocytosis. Altogether, our results reveal a mechanism for macropinocytic regulation and PPIs as potential modulators of EV levels, thus regulating their functions.

Adipose tissue­derived extracellular vesicles: Systemic messengers in health and disease (Review).

Adipose tissue (AT) is a complicated metabolic organ consisting of a heterogeneous population of cells that exert wide­ranging effects on the regulation of systemic metabolism and in maintaining metabolic homeostasis. Various obesity­related complications are associated with the development of dysfunctional AT. As an essential transmitter of intercellular information, extracellular vesicles (EVs) have recently been recognized as crucial in regulating multiple physiological functions. AT­derived extracellular vesicles (ADEVs) have been shown to facilitate cellular communication both inside and between ATs and other peripheral organs. Here, the role of EVs released from ATs in the homeostasis of metabolic and cardiovascular diseases, cancer, and neurological disorders by delivering lipids, proteins, and nucleic acids between different cells is summarized. Furthermore, the differences in the sources of ADEVs, such as adipocytes, AT macrophages, AT­derived stem cells, and AT­derived mesenchymal stem cells, are also discussed. This review may provide valuable information for the potential application of ADEVs in metabolic syndrome, cardiovascular diseases, cancer, and neurological disorders.

Type I interferon/STAT1 signaling regulates UBE2M-mediated antiviral innate immunity in a negative feedback manner.

Type I interferon (IFN-I) signaling is central to inducing antiviral innate immunity. However, the mechanisms for IFN-I signaling self-regulation are still largely unknown. Here, we report that RNA virus-infected macrophages with UBE2M deficiency produced decreased IFN-I expression in a RIG-I-dependent manner, causing an aggravated viral infection. Mechanistically, UBE2M inhibits RIG-I degradation by preventing the interaction of RIG-I and E3 ligase STUB1, resulting in antiviral IFN-I signaling activation. Simultaneously, IFN-I signaling-activated STAT1 facilitates the transcription of Trim21, leading to increased UBE2M degradation and blunted antiviral immunity. Translationally, oral administration of milk-derived extracellular vesicles containing RING domain-truncated TRIM21 (TRIM21-ΔRING) lacking E3 ligase activity efficiently transfers TRIM21-ΔRING into macrophages. TRIM21-ΔRING suppresses UBE2M degradation by competitively binding to UBE2M with TRIM21, thereby enhancing antiviral immunity. Overall, we reveal a negative feedback loop of IFN-I signaling and develop a reagent to improve innate immunity against RNA viruses.

UBE2M-mediated neddylation of TRIM21 regulates obesity-induced inflammation and metabolic disorders.

Inflammation is closely associated with obesity and related metabolic disorders. However, its origin during obesity is largely unknown. Here, we report that ubiquitin-conjugating enzyme E2M (UBE2M) is critical to obesity-related inflammation induced by macrophages. In mice with UBE2M-deficient macrophages, obesity, insulin resistance, and hepatic steatosis induced by a high-fat diet are greatly alleviated, an effect related to the decreased proinflammatory activity of macrophages due to reduced IL-1ß production. Mechanistically, UBE2M deficiency inhibits the neddylation of E3 ubiquitin ligase TRIM21 on K129/134, leading to reduced recruitment and ubiquitination-mediated degradation of E3 ubiquitin ligase VHL. Subsequently, VHL reduces HIF-1α-induced IL-1ß production by degrading HIF-1α. Targeting macrophage TRIM21 with Trim21 antisense oligonucleotide-loaded red blood cell extracellular vesicles effectively inhibits obesity-induced inflammation and related metabolic disorders. Thus, our results demonstrate that macrophage UBE2M is essential for obesity-induced inflammation and that TRIM21 is a proof-of-concept target for treating obesity and associated metabolic diseases.

Long-term exposure to imatinib reduced cancer stem cell ability through induction of cell differentiation via activation of MAPK signaling in glioblastoma cells.

Glioblastoma multiforme (GBM) was shown to harbor therapy-resistant cancer stem cells that were major causes of recurrence. PDGFR (platelet-derived growth factor receptor) and c-Kit (stem cell factor receptor) signaling play important roles in initiation and maintenance of malignant glioma. This study demonstrated that long-term culture with imatinib mesylate, the tyrosine kinase inhibitor against PDGFR and c-Kit resulted in reduced cancer stem cell ability in glioblastoma cells through cell differentiation. Derived from RG glioblastoma cells co-cultured with imatinib for 3 months, RG-IM cells showed distinct properties of cell cycle distribution and morphology in addition to significantly decreased ability to form aggregates and colonies in vitro and tumorigenicity in vivo. Increased expression of GFAP (astrocyte marker) and class III ß-tubulin isotype (Tuj1, neuron marker) were detected with morphology like neurons or astrocytes in RG-IM cells. Furthermore, decreased expression of stem cell markers, i.e., CD133, Oct-3/4, nestin, and Bmi1, and increased terminal neural cell markers, GFAP, Tuj1, etc., were identified in RG-IM at the mRNA level. All these markers were changed in RG cells when PDGFRB and c-Kit expression were double knocked down by siRNA. Cell differentiation agent, all-trans retinoic acid (ATRA) caused similar effect as that with imatinib in RG cells, while adding PDGF-B and SCF in RG-IM resulted in cell dedifferentiation to some extent. Moreover, differentiation in RG cells treated by imatinib or ATRA was mainly driven by MAPK signaling pathways. In summary, continuous inhibition on PDGFR and c-Kit signaling disturbed glioma stem cells biology in subsets of GBM cells and may have potentials in clinical applications.

Computed tomography in the size measurement of gastric gastrointestinal stromal tumors: Implication to risk stratification and "wait-and-see" tactics.

INTRODUCTION: This study aimed to compare the radiologic size of gastric gastrointestinal stromal tumors (GISTs) on computed tomography (CT) with the pathologic size in a Chinese population, and elucidate the potential significance of the CT size in the preoperative risk stratification. MATERIALS AND METHODS: The study enrolled 314 patients treated by endoscopic/surgical resection of gastric lesions that proved postoperatively to be GISTs. Bland-Altman analysis and intraclass correlation coefficient (ICC) were adopted to assess the size agreement between CT and pathology. Independent predictors of risk category underestimation and the optimal cut-off value of CT size were determined by logistic regression analysis and the receiver operating characteristic (ROC) curve. RESULTS: CT underestimated gastric GISTs size by 0.30 cm [95% confidence interval (CI): (-0.42, - 0.19); p < 0.001]. In the subgroup analysis, the size underestimation was 0.10 cm in GISTs ≤ 5 cm [95% CI: (-0.19, -0.01); p = 0.024]; and 0.75 cm in GISTs >5 cm [95% CI: (-1.05, 0.45), p < 0.001]. Though ICC values showed well reliability for the corresponding pathologic size, with 0.95 in all size, 0.86 in size ≤ 5 cm, and 0.92 in size >5 cm respectively. Risk underestimation by CT imaging mainly occurred in gastric GISTs with smaller size (≤5 cm; p = 0.010) and lower mitotic index (≤5 per 50 high-power fields; p = 0.011). CT size of 3.65 cm was defined as an absolute cut-off to differentiate intermediate/high-risk patients from low-risk group, with 87.5% sensitivity at a specificity of 57.8%. CONCLUSION: Preoperative CT underestimated the mean size by 0.30 cm in gastric GISTs. A CT size of 3.65 cm would facilitate the selection of potential intermediate/high-risk patients, instant intervention should be encouraged in the absence of contraindications.

Generation and characterization of a human induced pluripotent stem cell line (XWHNi001-A) derived from an Alzheimer's disease patient with mutation in the APP gene.

Mutations in the APP gene are popularly known as the second cause trigger the familial Alzheimer's disease (AD). We generated a human induced pluripotent stem cell (iPSC) line from the peripheral blood mononuclear cells isolated from an AD patient using non-integrative Sendai virus. The iPSC line highly expresses pluripotency markers, has the capacity to differentiate into the normal teratoma tissue, retains the APP mutation, and displays the normal karyotype. The iPSC line will provide a useful resource to study the pathogenesis and drugs screening of AD.

Association between family history and prognosis of patients with colorectal cancer: a systematic review and meta-analysis.

Background: A family history of colorectal cancer (CRC) increases the risk of developing CRC, and numerous studies have assessed the influence of family history on survival among CRC patients. However, the prognostic effect of a family history of CRC remains uncertain. The aim of this meta-analysis was to systematically assess the association between family history and CRC prognosis. Methods: A comprehensive literature search was performed in the PubMed, Embase, Medline, Web of Science and Scopus databases up to October 2021, based on the Population, Intervention, Comparator, Outcomes and Study designs framework. Two reviewers independently extracted data on baseline characteristics and outcomes from the included studies. The Newcastle-Ottawa Scale was used for quality assessment of each study. Either a fixed- or a random-effects model was used to calculate the pooled hazard ratio (HR). Results: Eighteen studies comprising 80,093 CRC patients were finally included in this meta-analysis. The Newcastle-Ottawa Scale scores of the included studies ranged from 4 to 8, and 12 studies were of high quality. A significant association between family history and improved overall survival was determined in the CRC patients (HR =0.89, 95% CI: 0.81-0.99) with significant heterogeneity (I2=65.7%, P<0.001). This effect was found in male CRC patients (HR 0.70, 95% CI: 0.56-0.88) but not females (HR =0.77, 95% CI: 0.54-1.09). The association between family history and disease-free survival was not significant (HR =0.94, 95% CI: 0.88-1.01) (I2=21.0%, P=0.263). However, a subgroup analysis supported the prognostic value of disease-free survival in patients with stage III CRC (pooled HR =0.78, 95% CI: 0.67-0.92). Discussion: In conclusion, a positive family history was associated with improved overall survival in CRC patients. It was also a favorable predictor of disease-free survival in patients with stage III CRC. These findings should be interpreted with caution because of limitations related to study quality and differences in the adjusted factors across studies.

Clinical Practice Guidelines for the Management of Behavioral and Psychological Symptoms of Dementia: A Systematic Review With AGREE II.

Background: High-quality clinical practice guidelines (CPGs) are important for the effective treatment of behavioral and psychological symptoms of dementia (BPSD). However, recommendations provided by different quality guidelines may lead to varied clinical practice outcomes. Objective: To assess the quality of available CPGs for the management of BPSD and summarize the best recommendations for treating BPSD. Methods: This was a systematic review of CPGs for the management of BPSD with data obtained from electronic databases and evaluated using the Appraisal of Guidelines for Research and Evaluation II instrument, consisting of six domains: "Scope and purpose", "Stakeholder involvement", "Rigor of development", "Clarity of presentation", "Applicability", and "Editorial independence". The criteria for high-quality guidelines were set as: the score of high-quality guidelines in the "Rigor of development" domain should be ≥60% and as well as a score of >60% in at least three other domains. High-quality guidelines were selected for recommendation extraction, and the final recommendations were formed in combination with the latest meta-analysis and randomized clinical-trial results. Results: In term of median scores in each domain for the six included CPGs, "Scope and purpose" (87.5%) scored better than all others, whereas "Applicability" (46.5%) was the domain with the lowest score. Four CPGs (2015 APA, 2018 NICE, 2018 CANADA, 2020 EAN) met the criteria of high-quality guidelines and were used to extract recommendations. From these four CPGs, nine specific recommendations related to the management of BPSD were summarized, of which seven were related to pharmacological treatment and two to non-pharmacological treatment. These recommendations covered the applicability of antipsychotic drugs, medication recommendations, withdrawal times, and several suitable non-pharmacological therapies. Conclusion: The quality of CPGs for the management of BPSD requires improvement, especially for the "Applicability" domain. For psychotic-like symptoms in dementia, the use of antipsychotics should be based on the individual's risk-benefit ratio, and the use of atypical antipsychotics seems to be a better choice. Non-pharmacological treatments may be suitable for emotional symptoms and sleep disorders. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020209204.

Tumor extracellular vesicles mediate anti-PD-L1 therapy resistance by decoying anti-PD-L1.

PD-L1+ tumor-derived extracellular vesicles (TEVs) cause systemic immunosuppression and possibly resistance to anti-PD-L1 antibody (αPD-L1) blockade. However, whether and how PD-L1+ TEVs mediate αPD-L1 therapy resistance is unknown. Here, we show that PD-L1+ TEVs substantially decoy αPD-L1 and that TEV-bound αPD-L1 is more rapidly cleared by macrophages, causing insufficient blockade of tumor PD-L1 and subsequent αPD-L1 therapy resistance. Inhibition of endogenous production of TEVs by Rab27a or Coro1a knockout reverses αPD-L1 therapy resistance. Either an increased αPD-L1 dose or macrophage depletion mediated by the clinical drug pexidartinib abolishes αPD-L1 therapy resistance. Moreover, in the treatment cycle with the same total treatment dose of αPD-L1, high-dose and low-frequency treatment had better antitumor effects than low-dose and high-frequency treatment, induced stronger antitumor immune memory, and eliminated αPD-L1 therapy resistance. Notably, in humanized immune system mice with human xenograft tumors, both increased αPD-L1 dose and high-dose and low-frequency treatment enhanced the antitumor effects of αPD-L1. Furthermore, increased doses of αPD-L1 and αPD-1 had comparable antitumor effects, but αPD-L1 amplified fewer PD-1+ Treg cells, which are responsible for tumor hyperprogression. Altogether, our results reveal a TEV-mediated mechanism of αPD-L1-specific therapy resistance, thus providing promising strategies to improve αPD-L1 efficacy.

Mesenchymal Stem Cells in Gastric Cancer: Vicious but Hopeful.

Tumor progression depends on the collaborative interactions between tumor cells and the surrounding stroma. First-line therapies direct against cancer cells may not reach a satisfactory outcome, such as gastric cancer (GC), with high risk of recurrence and metastasis. Therefore, novel treatments and drugs target the effects of stroma components are to be promising alternatives. Mesenchymal stem cells (MSC) represent the decisive components of tumor stroma that are found to strongly affect GC development and progression. MSC from bone marrow or adjacent normal tissues express homing profiles in timely response to GC-related inflammation signals and anchor into tumor bulks. Then the newly recruited "naïve" MSC would achieve phenotype and functional alternations and adopt the greater tumor-supporting potential under the reprogramming of GC cells. Conversely, both new-comers and tumor-resident MSC are able to modulate the tumor biology via aberrant activation of oncogenic signals, metabolic reprogramming and epithelial-to-mesenchymal transition. And they also engage in remodeling the stroma better suited for tumor progression through immunosuppression, pro-angiogenesis, as well as extracellular matrix reshaping. On the account of tumor tropism, MSC could be engineered to assist earlier diagnosis of GC and deliver tumor-killing agents precisely to the tumor microenvironment. Meanwhile, intercepting and abrogating vicious signals derived from MSC are of certain significance for the combat of GC. In this review, we mainly summarize current advances concerning the reciprocal metabolic interactions between MSC and GC and their underlying therapeutic implications in the future.

A Comparative Study of Structural and Metabolic Brain Networks in Patients With Mild Cognitive Impairment.

Background: Changes in the metabolic and structural brain networks in mild cognitive impairment (MCI) have been widely researched. However, few studies have compared the differences in the topological properties of the metabolic and structural brain networks in patients with MCI. Methods: We analyzedmagnetic resonance imaging (MRI) and fluoro-deoxyglucose positron emission tomography (FDG-PET) data of 137 patients with MCI and 80 healthy controls (HCs). The HC group data comes from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. The permutation test was used to compare the network parameters (characteristic path length, clustering coefficient, local efficiency, and global efficiency) between the two groups. Partial Pearson's correlation analysis was used to calculate the correlations of the changes in gray matter volume and glucose intake in the key brain regions in MCI with the Alzheimer's Disease Assessment Scale-Cognitive (ADAS-cog) sub-item scores. Results: Significant changes in the brain network parameters (longer characteristic path length, larger clustering coefficient, and lower local efficiency and global efficiency) were greater in the structural network than in the metabolic network (longer characteristic path length) in MCI patients than in HCs. We obtained the key brain regions (left globus pallidus, right calcarine fissure and its surrounding cortex, left lingual gyrus) by scanning the hubs. The volume of gray matter atrophy in the left globus pallidus was significantly positively correlated with comprehension of spoken language (p = 0.024) and word-finding difficulty in spontaneous speech item scores (p = 0.007) in the ADAS-cog. Glucose intake in the three key brain regions was significantly negatively correlated with remembering test instructions items in ADAS-cog (p = 0.020, p = 0.014, and p = 0.008, respectively). Conclusion: Structural brain networks showed more changes than metabolic brain networks in patients with MCI. Some brain regions with significant changes in betweenness centrality in both structural and metabolic networks were associated with MCI.