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Context.--Both salivary lymphadenomas (LADs) and Warthin-like mucoepidermoid carcinoma (MEC) contain components of epithelium and lymphoid stroma and their differential diagnosis can be difficult on the basis of morphology alone. Objective.--To clarify whether Warthin-like MEC was diagnosed as a LAD, and to compare their clinicopathologic features. Design.--A total of 16 LAD cases were analyzed for MAML2 rearrangement by using fluorescence in situ hybridization, and the clinical, histologic, immunohistochemical, and prognostic features were compared between MAML2 rearrangement-positive and MAML2 rearrangement-negative groups. Results.--Among the 16 cases investigated, 9 harbored a MAML2 rearrangement and were reclassified as Warthin-like MEC. The remaining 7 cases were classified as LADs with 1 nonsebaceous and 6 sebaceous cases. The patients with Warthin-like MEC had a wider age range (10-75 years) than the patients with LADs (36-68 years). Histologically, 2 of the 9 Warthin-like MECs (22.2%) showed focal invasion, whereas all the LADs had complete capsules. Warthin-like MECs exhibited a diverse epithelial cell morphology, including basaloid, glandular, cuboidal, epidermoid, with mucinous cells, although these cytologic features were seen only focally in some cases. Nonsebaceous LAD was composed of basaloid and glandular epithelial cells predominantly. In sebaceous LAD, the epithelial cells were composed of basaloid and large foamy sebaceous cells. In all cases, the stroma was composed mainly of lymphocytes accompanied by lymphoid follicles, although plasma cell infiltration could be much heavier in Warthin-like MEC. All the patients had a good outcome after a longer follow-up (3-166 months). Conclusions.--Warthin-like MEC can be misdiagnosed as a LAD owing to overlap in clinicopathologic features of the 2 entities. Careful histologic evaluation and detection of MAML2 rearrangement can facilitate their differential diagnosis. (Arch Pathol Lab Med. 2021;145:744-752; doi: 10.5858/arpa.2019-0702-OA, Lymphadenomas (LADs) are rare benign salivary gland tumors comprising epithelial cells, with or without sebaceous differentiation, intermixed with intense, reactive lymphoid proliferation. (1) Since their first description in 1960 by [...]

Birth weight is a complex multifactorial trait relevant to health states and disease risks in later life. The placenta is essential for proper fetal growth and facilitates gas, nutrient, and waste exchange between the mother and developing fetus. How changes in placental DNA methylation affect fetal birth weight remains to be fully elucidated. In this study, we used whole-genome bisulfite sequencing and RNA sequencing to reveal a global map of DNA methylation and gene expression changes between the placentas of highest birth weight and lowest birth weight piglets in the same litters. The transcriptome analysis identified 1682 differential expressed genes and revealed key transcriptional properties in distinct placentas. We also identified key transcription factors that may drive the differences in DNA methylome patterns between placentas. The decrease in DNA methylation level in the promoter was associated with the transcriptional activation of genes associated with angiogenesis, extracellular matrix remodeling, and transmembrane transport. Our results revealed the regulatory role of DNA methylation in gene transcription activity leading to the differences in placental morphological structures and birth weights of piglets. These results could provide novel clues to clarify the underlying regulatory mechanisms of placental development and fetal growth. [ABSTRACT FROM AUTHOR]

AIM: To investigate the role of Ywhab in the growth of mouse B-cell lymphoma, and to explore the potential underlying mechanisms. METHODS : The correlation between Ywhab and human diffuse large B-cell lymphoma (DLBCL) was investigated by bioinformatics analysis. Infection with retroviral vector was performed to establish stable mouse B-cell lymphoma 38B9 cell line with overexpression of Ywhab gene, which was verified by RT-qPCR and Western blot. The impact of Ywhab overexpression on 38B9 cell growth both in vitro and in vivo was detected by cell counting, CCK-8 assay, and subcutaneous tumor loading experiments. The expression of apoptosis-related proteins was detected by RT-qPCR and Western blot. Co-immunoprecipitation combined with mass spectrometry (CoIP-MS) was employed to search for proteins specifically binding to Ywhab gene product 14-3-3β, which was confirmed by Western blot and molecular docking analysis. RESULTS: The Ywhab gene exhibited low expression in DLBCL, which was correlated with poor clinical prognosis of DLBCL patients. Compared with normal mouse bone marrow B cells, Ywhab expression was low in 38B9 cells. Overexpression of Ywhab induced apoptosis of 38B9 cells both in vitro and in vivo, promoted the expression of pro-apoptotic proteins Puma, Noxa and Bax at both mRNA and protein levels, and inhibited the mRNA and protein expression of anti-apoptotic protein Bcl2 (P<0. 05). The 14-3-3β protein specifically bound to Hsp90aa1 and reduced Hsp90aa1 protein levels, thereby suppressing the growth of 38B9 cells. CONCLUSION: Ywhab promotes the apoptosis of B-cell lymphoma cells by binding to Hsp90aa1 and thereby inhibiting the function of Hsp90aa1. [ABSTRACT FROM AUTHOR]

Metastasis is the leading cause of death in patients with breast, lung, and head and neck cancers. However, the molecular mechanisms underlying metastases in these cancers remain unclear. We found that the p90 ribosomal S6 kinase 2 (RSK2)-cAMP response element-binding protein (CREB) pathway is commonly activated in diverse metastatic human cancer cells, leading to up-regulation of a CREB transcription target Fascin-1. We also observed that the protein expression patterns of RSK2 and Fascin-1 correlate in primary human tumor tissue samples from head and neck squamous cell carcinoma patients. Moreover, knockdown of RSK2 disrupts filopodia formation and bundling in highly invasive cancer cells, leading to attenuated cancer cell invasion in vitro and tumor metastasis in vivo, whereas expression of Fascin-1 significantly rescues these phenotypes. Furthermore, targeting RSK2 with the small molecule RSK inhibitor FMK-MEA effectively attenuated the invasive and metastatic potential of cancer cells in vitro and in vivo, respectively. Taken together, our findings for the first time link RSK2-CREB signaling to filopodia formation and bundling through the up-regulation of Fascin-1, providing a proinvasive and prometastatic advantage to human cancers. Therefore, protein effectors of the RSK2-CREB-Fascin-1 pathway represent promising biomarkers and therapeutic targets in the clinical prognosis and treatment of metastatic human cancers.

How invasive and metastatic tumor cells evade anoikis induction remains unclear. We found that knockdown of RSK2 sensitizes diverse cancer cells to anoikis induction, which is mediated through phosphorylation targets including apoptosis signal-regulating kinase 1 (ASK1) and cyclic AMP (cAMP) response element-binding protein (CREB). We provide evidence to show that RSK2 inhibits ASK1 by phosphorylating S83, T1109, and T1326 through a novel mechanism in which phospho-T1109/T1326 inhibits ATP binding to ASK1, while phospho-S83 attenuates ASK1 substrate MKK6 binding. Moreover, the RSK2→CREB signaling pathway provides antianoikis protection by regulating gene expression of protein effectors that are involved in cell death regulation, including the antiapoptotic factor protein tyrosine kinase 6 (PTK6) and the proapoptotic factor inhibitor-of-growth protein 3 (ING3). PTK6 overexpression or ING3 knockdown in addition to ASK1 knockdown further rescued the increased sensitivity to anoikis induction in RSK2 knockdown cells. These data together suggest that RSK2 functions as a signal integrator to provide antianoikis protection to cancer cells in both transcription-independent and -dependent manners, in part by signaling through ASK1 and CREB, and contributes to cancer cell invasion and tumor metastasis.

Transient structures play a wide range of vital roles in biological systems. Different from static structures that form the skeleton of bio‐tissues, transient structures only occur at certain spatial and temporal scales to undertake their duties in the life circle. Despite the significant progress in the field of artificial molecular self‐assembly studies, it still remains challenging to construct functional transient structures. Herein, the shaping of transient coordinating self‐assembled structures and their fluorescence is reported via host‐guest interaction that disfavors the assembly. The host‐guest interaction between the luminescent ligand and cyclodextrin drastically changes the kinetics of the coordinating self‐assembly, enabling the formation of transient structures. Different from the static equilibrium one with typical monomer emission in the UV region, the transient self‐assembly forms excimers, leading to visible emission. More intriguingly, the life cycle of the transient structures can be easily modulated by varying the host‐guest ratio, ligand‐metal ratio, as well as temperature. This makes it possible to create living patterns that mimic the growth of plants at different life stages. It is therefore envisioned that the creation of transient molecular self‐assembly will open a new paradigm in the field of molecular self‐assembly featuring advanced materials with dynamic functions. [ABSTRACT FROM AUTHOR]

The calcium-sensing receptor (CaSR) is a family C G-protein-coupled receptor1 (GPCR) that has a central role in regulating systemic calcium homeostasis2,3. Here we use cryo-electron microscopy and functional assays to investigate the activation of human CaSR embedded in lipid nanodiscs and its coupling to functional Gi versus Gq proteins in the presence and absence of the calcimimetic drug cinacalcet. High-resolution structures show that both Gi and Gq drive additional conformational changes in the activated CaSR dimer to stabilize a more extensive asymmetric interface of the seven-transmembrane domain (7TM) that involves key protein–lipid interactions. Selective Gi and Gq coupling by the receptor is achieved through substantial rearrangements of intracellular loop 2 and the C terminus, which contribute differentially towards the binding of the two G-protein subtypes, resulting in distinct CaSR–G-protein interfaces. The structures also reveal that natural polyamines target multiple sites on CaSR to enhance receptor activation by zipping negatively charged regions between two protomers. Furthermore, we find that the amino acid l-tryptophan, a well-known ligand of CaSR extracellular domains, occupies the 7TM bundle of the G-protein-coupled protomer at the same location as cinacalcet and other allosteric modulators. Together, these results provide a framework for G-protein activation and selectivity by CaSR, as well as its allosteric modulation by endogenous and exogenous ligands. Cryo-electron microscopy structures of the human calcium-sensing receptor in complex with Gi and Gq proteins reveal how this receptor activates distinct G protein subtypes and how its function is modulated by a variety of ligands. [ABSTRACT FROM AUTHOR]

Cyclodextrins (CDs) are widely used macrocycles in supramolecular assembly due to their easy availability, versatile functionality and excellent biocompatibility. Although they are well-known for forming host–guest complexes with a wide range of guests and this host–guest chemistry has long been utilized in industry and academia, new opportunities have arisen in recent years, particularly in supramolecular assembly. In the present review, we will first provide a basic introduction to CDs and then summarize their emerging roles in the fields of supramolecular chemistry and materials. This includes their involvement in hybrid frameworks with inorganic components such as metal ions and polyoxometalates, crystalline self-assembly with amphiphilic molecules, and their new possibility of "catassembly" and induced chiral supramolecular structures that have previously been overlooked. Finally, we will comment on the future perspectives of CDs to inspire more ideas and efforts, with the aim of promoting diverse applications of CDs in supramolecular materials. [ABSTRACT FROM AUTHOR]