Gastric cancer is the third leading cause of cancer-related deaths worldwide. Over 95% of gastric cancers are adenocarcinomas, which are typically classified based on anatomic location and histologic type. Gastric cancer generally carries a poor prognosis because it is often diagnosed at an advanced stage. Systemic therapy can provide palliation, improved survival, and enhanced quality of life in patients with locally advanced or metastatic disease. The implementation of biomarker testing, especially analysis of HER2 status, microsatellite instability (MSI) status, and the expression of programmed death-ligand 1 (PD-L1), has had a significant impact on clinical practice and patient care. Targeted therapies including trastuzumab, nivolumab, and pembrolizumab have produced encouraging results in clinical trials for the treatment of patients with locally advanced or metastatic disease. Palliative management, which may include systemic therapy, chemoradiation, and/or best supportive care, is recommended for all patients with unresectable or metastatic cancer. Multidisciplinary team management is essential for all patients with localized gastric cancer. This selection from the NCCN Guidelines for Gastric Cancer focuses on the management of unresectable locally advanced, recurrent, or metastatic disease.

Chronic lymphocytic leukemia (CLL) B cells express BR3, the specific receptor for the B cell-activating factor of tumor necrosis factor family (BAFF). CLL cells also express 2 other receptors for BAFF, namely B-cell maturation antigen (BCMA) and the transmembrane activator and calcium modulator and cyclophilin ligandinteractor (TACI), which also bind a proliferation-inducing ligand (APRIL). We found that signaling through BR3, but not BCMA or TACI, activated the alternative nuclear IntroductionThe B cell-activating factor of tumor necrosis factor (TNF) family (BAFF, also known as BlyS, TALL-1, zTNF4, and THANK) is a potent regulator of normal B-cell development and function. 1-3 A proliferation-inducing ligand (APRIL, also termed TALL-2 and TRAD-1) also is a member of the TNF family and shares significant homology with BAFF. APRIL has been found to stimulate the growth of tumor cells and the proliferation of primary lymphocytes. 3-5 BAFF and APRIL bind 2 receptors of the TNF superfamily, B-cell maturation antigen (BCMA) and transmembrane activator or the calcium modulator and cyclophilin ligandinteractor (TACI). 6-8 BAFF, but not APRIL, binds a third receptor known as BAFF receptor (BAFF-R or BR3). 9,10 BCMA, TACI, and BR3 are expressed on normal B lymphocytes. 9,11,12 Neoplastic B cells in chronic lymphocytic leukemia (CLL) also express these receptors for BAFF and APRIL, which, when ligated, can promote CLL cell survival in vitro. [13][14][15][16][17][18] Furthermore, nurselike cells (NLCs), which can protect CLL cells in vitro and presumably in vivo, 19,20 express high levels of BAFF and APRIL, accounting in part for their capacity to promote CLL cell survival in a paracrine fashion. 21 Kern et al 14 found that CLL cells themselves might express BAFF or APRIL, suggesting that these factors also might function in an autocrine fashion to promote leukemia cell survival. 14 Understanding the mechanisms whereby BAFF and APRIL support CLL survival could lead to the development of inhibitors to BAFF and APRIL signaling that may be therapeutic in patients with this disease.Many members of the TNF superfamily trigger the activation of nuclear factor of B (NF-B). Recent studies have revealed that 2 NF-B pathways, the canonical pathway and the alternative pathway, regulate the activity of NF-B. 22,23 Activation of the canonical NF-B pathway proceeds through the degradation of the inhibitor of NF-B␣ (IB␣), which is induced after its phosphorylation by the ␤ subunit of the IB kinase (IKK) complex (IKK␤). 24 Degradation of IB␣ leads to the nuclear translocation of active NF-B heterodimers (composed of p50, p65, and/or c-Rel), where they can affect changes in gene expression. Activation of the alternative NF-B pathway results from processing of NF-B2/ p100 to p52, which is triggered by the phosphorylation of NF-B2/p100 by the ␣ subunit of the IKK complex (IKK␣). 25 This allows for nuclear translocation of p52 along with RelB, where together they can influence the expression of genes that are distinct from those regulated b...

We report the primary structures of human and rabbit brush border membrane beta‐glycosidase complexes (pre‐pro‐lactase‐phlorizin hydrolase, or pre‐pro‐LPH, EC 3.2.1.23‐62), as deduced from cDNA sequences. The human and rabbit primary translation products contain 1927 and 1926 amino acids respectively. Based on the data, as well as on peptide sequences and further biochemical data, we conclude that the proteins comprise five domains: (i) a cleaved signal sequence of 19 amino acids; (ii) a large ‘pro’ portion of 847 amino acids (rabbit), none of which appears in mature, membrane‐bound LPH; (iii) the mature LPH, which contains both the lactase and phlorizin hydrolase activities in a single polypeptide chain; (iv) a membrane‐spanning hydrophobic segment near the carboxy terminus, which serves as membrane anchor; and (v) a short hydrophilic segment at the carboxy terminus, which must be cytosolic (i.e. the protein has an Nout‐Cin orientation). The genes have a 4‐fold internal homology, suggesting that they evolved by two cycles of partial gene duplication. This repetition also implies that parts of the ‘pro’ portion are very similar to parts of mature LPH, and hence that the ‘pro’ portion may be a water‐soluble beta‐glycosidase with another cellular location than LPH. Our results have implications for the decline of LPH after weaning and for human adult‐type alactasia, and for the evolutionary history of LPH.

Expression of B cell-activating factor (BAFF), a critical B cell survival factor, is elevated in autoimmune and lymphoproliferative disorders. Mice overproducing BAFF develop systemic lupus erythematosus (SLE)-like disease and exhibit B cell activation of classical and alternative NF-kappaB-signaling pathways. We used a genetic approach and found that both NF-kappaB-signaling pathways contributed to disease development but act through distinct mechanisms. Whereas BAFF enhanced long-term B cell survival primarily through the alternative, but not the classical, NF-kappaB pathway, it promoted immunoglobulin class switching and generation of pathogenic antibodies through the classical pathway. Activation of the alternative NF-kappaB pathway resulted in integrin upregulation, thereby retaining autoreactive B cells in the splenic marginal zone, a compartment that contributes to their survival. Thus, both classical and alternative NF-kappaB signaling are important for development of lupus-like disease associated with BAFF overproduction. The same mechanisms may be involved in the pathogenesis of human SLE.

Chronic inflammation contributes to carcinogenesis, but the underlying mechanisms are poorly understood. We report that aged granulocyte-macrophage colony stimulating factor (GM-CSF)-deficient mice develop a systemic lupus erythematosis (SLE)-like disorder associated with the impaired phagocytosis of apoptotic cells. Concurrent deficiency of interferon (IFN)-γ attenuates the SLE, but promotes the formation of diverse hematologic and solid neoplasms within a background of persistent infection and inflammation. Whereas activated B cells show a resistance to fas-induced apoptosis, antimicrobial therapy prevents lymphomagenesis and solid tumor development. These findings demonstrate that the interplay of infectious agents with cytokine-mediated regulation of immune homeostasis is a critical determinant of cancer susceptibility.