CXCR4 is a pleiotropic chemokine receptor which acts through its ligand CXCL12 to regulate diverse physiological processes. CXCR4/CXCL12 axis plays a pivotal role in proliferation, invasion, dissemination and drug resistance in multiple myeloma (MM). Apart from its role in homing, CXCR4 also affects MM cell mobilization and egression out of the bone marrow (BM) which is correlated with distant organ metastasis. Aberrant CXCR4 expression pattern is associated with osteoclastogenesis and tumor growth in MM through its cross talk with various important cell signalling pathways. A deeper insight into understanding of CXCR4 mediated signalling pathways and its role in MM is essential to identify potential therapeutic interventions. The current therapeutic focus is on disrupting the interaction of MM cells with its protective tumor microenvironment where CXCR4 axis plays an essential role. There are still multiple challenges that need to be overcome to target CXCR4 axis more efficiently and to identify novel combination therapies with existing strategies. This review highlights the role of CXCR4 along with its significant interacting partners as a mediator of MM pathogenesis and summarizes the targeted therapies carried out so far.

The role of the transforming growth factor (TGF)-β pathway in myocardial fibrosis is well recognized. However, the precise role of this signaling axis in cardiomyocyte (CM) biology is not defined. In TGF-β signaling, SMAD4 acts as the central intracellular mediator. To investigate the role of TGF-β signaling in CM biology, the authors deleted SMAD4 in adult mouse CMs. We demonstrate that CM-SMAD4-dependent TGF-β signaling is critical for maintaining cardiac function, sarcomere kinetics, ion-channel gene expression, and cardiomyocyte survival. Thus, our findings raise a significant concern regarding the therapeutic approaches that rely on systemic inhibition of the TGF-β pathway for the management of myocardial fibrosis.

Longevity in medicine can be defined as a long life without mental or physical deficits. This can be prevented by Alzheimer\'s disease (AD). Current conventional AD treatments only alleviate the symptoms without reversing AD progression. Recent studies demonstrated that Panax ginseng extract improves AD symptoms in patients with AD, and the two main components of ginseng might contribute to AD amelioration. Ginsenosides show various AD-related neuroprotective effects. Gintonin is a newly identified ginseng constituent that contains lysophosphatidic acids and attenuates AD-related brain neuropathies. Ginsenosides decrease amyloid β-protein (Aβ) formation by inhibiting β- and γ-secretase activity or by activating the nonamyloidogenic pathway, inhibit acetylcholinesterase activity and Aβ-induced neurotoxicity, and decrease Aβ-induced production of reactive oxygen species and neuroinflammatory reactions. Oral administration of ginsenosides increases the expression levels of enzymes involved in acetylcholine synthesis in the brain and alleviates Aβ-induced cholinergic deficits in AD models. Similarly, gintonin inhibits Aβ-induced neurotoxicity and activates the nonamyloidogenic pathway to reduce Aβ formation and to increase acetylcholine and choline acetyltransferase expression in the brain through lysophosphatidic acid receptors. Oral administration of gintonin attenuates brain amyloid plaque deposits, boosting hippocampal cholinergic systems and neurogenesis, thereby ameliorating learning and memory impairments. It also improves cognitive functions in patients with AD. Ginsenosides and gintonin attenuate AD-related neuropathology through multiple routes. This review focuses research demonstrating that ginseng constituents could be a candidate as an adjuvant for AD treatment. However, clinical investigations including efficacy and tolerability analyses may be necessary for the clinical acceptance of ginseng components in combination with conventional AD drugs.

Gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN), considered a heterogeneous neoplasia, exhibit ill-defined pathobiology and protean symptomatology and are ubiquitous in location. They are difficult to diagnose, challenging to manage, and outcome depends on cell type, secretory product, histopathologic grading, and organ of origin. A morphologic and molecular genomic review of these lesions highlights tumor characteristics that can be used clinically, such as somatostatin-receptor expression, and confirms features that set them outside the standard neoplasia paradigm. Their unique pathobiology is useful for developing diagnostics using somatostatin-receptor targeted imaging or uptake of radiolabeled amino acids specific to secretory products or metabolism. Therapy has evolved via targeting of protein kinase B signaling or somatostatin receptors with drugs or isotopes (peptide-receptor radiotherapy). With DNA sequencing, rarely identified activating mutations confirm that tumor suppressor genes are relevant. Genomic approaches focusing on cancer-associated genes and signaling pathways likely will remain uninformative. Their uniquely dissimilar molecular profiles mean individual tumors are unlikely to be easily or uniformly targeted by therapeutics currently linked to standard cancer genetic paradigms. The prevalence of menin mutations in pancreatic NEN and P27KIP1 mutations in small intestinal NEN represents initial steps to identifying a regulatory commonality in GEP-NEN. Transcriptional profiling and network-based analyses may define the cellular toolkit. Multianalyte diagnostic tools facilitate more accurate molecular pathologic delineations of NEN for assessing prognosis and identifying strategies for individualized patient treatment. GEP-NEN remain unique, poorly understood entities, and insight into their pathobiology and molecular mechanisms of growth and metastasis will help identify the diagnostic and therapeutic weaknesses of this neoplasia.

Dab2 is an adapter protein involved in receptor-mediated signaling, endocytosis, cell adhesion, hematopoietic cell differentiation, and angiogenesis. It plays a pivotal role in controlling cellular homeostasis. In the immune system, the Dab2 is a Foxp3 target gene and is required for regulatory T (Treg) cell function. Dab2 expression and its biological function in dendritic cells (DCs) have not been described. In this study, we found that Dab2 was significantly induced during the development of mouse bone marrow (BM)-derived DCs (BMDCs) and human monocyte-derived DCs (MoDCs). Even in a steady state, Dab2 was expressed in mouse splenic DCs (spDCs). STAT5 activation, Foxp3 expression, and hnRNPE1 activation mediated by PI3K/Akt signaling were required for Dab2 expression during GM-CSF-derived BMDC development regardless of TGF-β signaling. Dab2-silencing was accompanied by enhanced IL-12 and IL-6 expression, and an improved capacity of DC for antigen uptake, migration and T cell stimulation, which generated strong CTL in vaccinated mice. Vaccination with Dab2-silenced DCs inhibited tumor growth more effectively than did vaccination with wild type DCs. Dab2-overexpression abrogated the efficacy of the DC vaccine in DC-based tumor immunotherapy. These data strongly suggest that Dab2 might be an intrinsic negative regulator of the immunogenicity of DCs, thus might be an attractive molecular target to improve DC vaccine efficacy.

While most attention has been focused on physiologically generated blebs, the molecular mechanisms for fixation-induced cell blebbing are less investigated. We show that protein-fixing (e.g. aldehydes and picric acid) but not lipid-stabilizing (e.g. OsO4 and KMnO4) fixatives induce blebbing on spread cells. We also show that aldehyde fixation may induce the loss or delocalization of phosphatidylinositol 4,5-bisphosphate (PIP2) in the plasma membrane and that the asymmetric distribution of fixation-induced blebs on spread/migrating cells coincides with that of PIP2 on the cells prefixed by lipid-stabilizing fixatives (e.g., OsO4). Moreover, fixation induces blebbing less readily on PIP2-elevated spread cells but more readily on PIP2-lowered or lipid raft-disrupted spread cells. Our data suggest that fixation-induced lowering of PIP2 level at cytoskeleton-attaching membrane sites causes bleb formation via local breakdown of the membrane-cytoskeleton coupling.