Primary Hepatoid Adenocarcinoma of Gallbladder With MB21D2/GALNT12/ARID2 Mutations: A Case Report

BackgroundPrimary hepatoid adenocarcinoma of the gallbladder is a relatively rare type of extrahepatic adenocarcinoma. The genetic changes involved in this type of adenocarcinoma were unexplained so far. We reported a rare case of primary hepatoid adenocarcinoma of gallbladder with Mab-21 domain containing 2 (MB21D2), polypeptide N-acetylgalactosaminyltransferase 12 (GALNT12), and AT-rich interaction domain 2 (ARID2) mutations, which was confirmed after surgical resection pathologically.Case SummaryA 69-year-old female with distention of hypogastrium and constipation received enema treatment, but ineffectively. No abnormalities were found on relevant physical examination. Then, the CT and MRI demonstrated a 3.3–4-cm soft tissue mass shadow in the neck of the gallbladder. The primary lesions consisted of two components: high-grade intraepithelial neoplasia of glands and hepatoid glands microscopically after laparoscope cholecystectomy. Immunohistochemical staining showed the sameness and difference of the two areas. Furthermore, tumor mutational burden (TMB) shows that the MB21D2, GALNT12, and ARID2 genes were mutated.ConclusionThis is the first report of primary hepatoid adenocarcinoma of the gallbladder with MB21D2, GALNT12, and ARID2 mutations. This will provide a theoretical basis for genetic changes in rare tumors.

Combinatorial Analysis of AT-Rich Interaction Domain 1A and CD47 in Gastric Cancer Patients Reveals Markers of Prognosis

Background: The AT-rich interaction domain 1A (ARID1A) is thought to be a tumor suppressive gene, and most of its mutations result in loss of expression of ARID1A protein. Combined with SIRPα on the surface of macrophages, CD47 on the surface of cancer cells can send an antiphagocytic “Don’t eat me” signal to the immune system that helps to avoid immune surveillance. However, the relationship between ARID1A and CD47 expression and their prognostic value in gastric cancer (GC) are still unknown.Methods: In this study, we evaluated ARID1A and CD47 expression in 154 GC patients’ tissues using tissue microarray. Expressions of ARID1A and CD47 in GC cell lines were determined by western blot and quantitative reverse transcriptase–polymerase chain reaction (qRT-PCR) techniques, and cell membranous CD47 expression was quantified by flow cytometry. In addition, chromatin immunoprecipitation (ChIP)–qPCR was used to determine the aspects of regulation of CD47 by ARID1A. The proportions of tumor-infiltrating immune cells were estimated on The Cancer Genome Atlas (TCGA) data set by using quanTIseq and EPIC algorithms. The infiltration of M1-polarized macrophages, M2-polarized macrophages, and regulatory T cells (Tregs) in GC tissues was determined by multispectral immunofluorescence.Results: A significant correlation was found between loss of ARID1A and high expression of CD47 at protein level in GC. By integrating 375 bulk RNA sequencing samples from TCGA data set, we found that mutated ARID1A correlated with high CD47 expression. In GC cell lines, knockdown of ARID1A significantly increased CD47 expression both at protein and mRNA levels as measured by western blot, qRT-PCR, and flow cytometry. Moreover, ChIP-qPCR revealed that CD47 was a direct downstream target gene of ARID1A in GC. Utilizing univariate and multivariate survival analyses, we found that patients with ARID1AlossCD47high expression had a worse prognosis. Estimation of infiltrating immune cells on TCGA data set showed that a higher infiltration proportion of M2 macrophages and Tregs was found in ARID1AmutatedCD47high expression subgroup. Furthermore, application of multispectral immunofluorescence revealed a higher infiltration proportion of M2 macrophages and Tregs in ARID1AlossCD47high GC tissues.Conclusion: Loss of ARID1A is strongly correlated with high CD47 expression in GC, and combination of ARID1A and CD47 is a promising prognosis factor in GC.

ARID1A Variations in Cholangiocarcinoma: Clinical Significances and Molecular Mechanisms

Cholangiocarcinoma (CCA), a high mortality malignant carcinoma characterized by advanced disease and frequent recurrence, constitutes a major challenge for treatment and prognosis. AT-rich interaction domain 1A (ARID1A) variation is a distinct genetic entity in CCA, getting mounting concerns recently. Here, we comprehensively reviewed the clinical significance and molecular mechanisms of ARID1A alterations in CCA. Based on the independent data derived from 29 relevant studies, the variation rate of ARID1A in intrahepatic and extrahepatic CCA is reported at 6.9–68.2% and 5–55%, respectively. Most of the included studies (28/29, 96.6%) suggest that ARID1A serves as a tumor suppressor in CCA. ARID1A variation may be an important prognostic indicator to predict disease mortality, metastasis, and recurrence in patients with CCA. Multifactorial molecular mechanisms are involved in the relationship between ARID1A variations and the pathogenesis and pathophysiology of CCA, including disruption of the cell cycle, chromatin remodeling, oxidative stress damage, DNA hypermethylation, and the interaction of multiple genes being affected. This review describes that ARID1A variation might be a potential diagnostic and prognostic biomarker for CCA. Future diagnoses and treatments targeting ARID1A hint towards a precision medicine strategy in the management of CCA.

Corner states in a second-order mechanical topological insulator

Demonstration of topological boundary modes in elastic systems has attracted a great deal of attention over the past few years due to its unique protection characteristic. Recently, second-order topological insulators have been proposed in manipulating the topologically protected localized states emerging only at corners. Here, we numerically and experimentally study corner states in a two-dimensional phononic crystal, namely a continuous elastic plate with embedded bolts in a hexagonal pattern. We create interfacial corners by adjoining trivial and non-trivial topological configurations. Due to the rich interaction between the bolts and the continuous elastic plate, we find a variety of corner states of and devoid of topological origin. Strikingly, some of the corner states are not only highly-localized but also tunable. Taking advantage of this property, we experimentally demonstrate asymmetric corner localization in a Z-shaped domain wall. This finding could create interest in exploration of tunable corner states for the use of advanced control of wave localization.

Uncovering the dosage-dependent roles of Arid1a in gastric tumorigenesis for combinatorial drug therapy

Gastric cancer (GC) is one of the most common deadly cancers in the world. Although patient genomic data have identified AT-rich interaction domain 1A (ARID1A), a key chromatin remodeling complex subunit, as the second most frequently mutated gene after TP53, its in vivo role and relationship to TP53 in gastric tumorigenesis remains unclear. Establishing a novel mouse model that reflects the ARID1A heterozygous mutations found in the majority of human GC cases, we demonstrated that Arid1a heterozygosity facilitates tumor progression through a global loss of enhancers and subsequent suppression of the p53 and apoptosis pathways. Moreover, mouse genetic and single-cell analyses demonstrated that the homozygous deletion of Arid1a confers a competitive disadvantage through the activation of the p53 pathway, highlighting its distinct dosage-dependent roles. Using this unique vulnerability of Arid1a mutated GC cells, our combined treatment with the epigenetic inhibitor, TP064, and the p53 agonist, Nutlin-3, inhibited growth of Arid1a heterozygous tumor organoids, providing a novel therapeutic option for GC.

Active Learning: From Flipped Lectures to the Covid-19 Era

The use of flipped lectures and Active Learning has been explored in first year lectures for several years. Learning Catalytics software has been used to facilitate Peer-2-Peer learning in the Active Learning sessions. Several lessons were learned during these sessions which were important as we moved into delivering online material much more comprehensively. Bringing interaction to the lectures that were delivered live (synchronous sessions) was important to staff. Several technical solutions for producing online videos of high quality were brought into broader use. New teaching formats including a 'radio show' have been introduced to ensure that rich interaction with the students is possible with large groups.

Weighing the Costs

This chapter explores the Carter administration's approach to Argentina, driven by a rich interaction between advocates and government officials in Buenos Aires and Washington. Argentina was the site of some of the Carter administration's most sustained and vigorous human rights efforts, yet it also revealed the limits of influence and competing priorities among administration officials and U.S. human rights groups. In Argentina, tensions arose around the dual objectives of U.S. policy: to defend human rights by distancing itself from dictatorships and to engage with repressive regimes to improve specific human rights problems. The Carter administration had built its foreign policy around the premise that the promotion and support of human rights would serve the national interest by building the United States' stature and influence in the international system. With Argentina, however, its human rights initiatives increasingly appeared to conflict with other national interests, particularly economic growth and new security concerns. With a struggling economy at home, the potential loss of trade and jobs due to human rights legislation curtailing international investment led some to question how this policy served the national interest.

Modern Macroeconomics and Heterogeneity

Modern macroeconomics has evolved from focusing just on the dynamics of aggregates, such as income, consumption and savings, to the dynamics of the distributions that add up to those aggregates. This is a consequence of theoretical contributions and increasing data availability and computational power. Though contributions regarding heterogeneity in macroeconomics can be traced back to the first half of the 20th century, it is only by the 2010s that we evolved towards a framework where there is a rich interaction between macroeconomic aggregates and their distributions that goes both ways. This special edition focused on contributions that build on such framework to study open questions regarding the impact of fiscal shocks on output, the impact of investment‑ specific technological change on inequality, optimal tax structures, and the impact of the COVID‑ 19 pandemic on the distribution of earnings.