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Second cancers are a substantial clinical problem in survivorship. A genome-wide association study (GWAS) in survivors of Hodgkin's lymphoma treated with radiotherapy now identifies a region of susceptibility on chromosome 6q21 (pages 941–943), paving the way for further investigations of the complex interplay between genetic susceptibility and environmental exposures involved in the development of second cancers.
The ribosomal protein RPL11 can block cell growth by boosting function of the tumor suppressor p53 in response to ribosomal stress, but the connection of this role with cancer has been obscure. New findings show that the nucleolar protein PICT1 can sequester RPL11, impairing p53 activation and favoring tumor growth (pages 944–951).
Certain human leukocyte antigen (HLA) alleles are associated with vigorous human immunodeficiency virus (HIV)-specific CD8+ T cell responses and good clinical outcomes. A new study suggests that CD8+ T cell–mediated killing of regulatory CD4+ T cells may partially explain how people with these protective alleles control HIV-1 replication (pages 989–995).
How B cell tolerance is retained during somatic hypermutation in germinal centers is incompletely understood. Two studies now show that Foxp3+ regulatory T cells undergo functional specialization to limit the magnitude of the germinal center response, and they may contribute to our understanding of how germinal center–mediated autoimmunity is prevented (pages 975–982 and 983–988).
Spontaneous calcium release from intracellular stores can trigger irregular heart beats and sudden death. A new study shows that the heart failure drug carvedilol prevents irregular heart beats by a unique action on calcium release channels (pages 1003–1009).
For many years, investigators have been searching for an elusive circulating factor that could cause the common kidney disease focal segmental glomerulosclerosis (FSGS). The finding that a circulating, soluble form of the urokinase receptor (suPAR) can activate podocyte β3 integrin, leading to FSGS pathology (pages 952–960), provides new insights into this disease and may have important clinical implications.
To repair the immune-mediated demyelination that occurs in people with multiple sclerosis, strategies to enhance remyelination are being considered as a possible therapy. A new study shows that inhibition of death receptor 6 (DR6) signaling increases the maturation and survival of oligodendrocytes, thus promoting remyelination in rodent models of demyelination (pages 816–821). Blocking DR6 might provide new therapeutic opportunities for the treatment of demyelinating diseases.
Despite intensive study, the mechanisms of pathogenesis in inflammatory bowel diseases (IBDs) remain poorly understood. An innate T helper type 17 (TH17) response that requires nucleotide oligomerization domain (Nod)-like receptors and is primed by commensal bacteria is now shown to be crucial for controlling intestinal bacterial pathogens in a mouse model (pages 837–844). Thus, dysregulation of this protective immune response may be important in IBD development.
A recent study challenges the view that radiation-induced apoptosis is beneficial in tumor therapy by showing that caspase 3–mediated apoptosis in response to ionizing radiation activates a growth signaling cascade in tumor cells, thereby stimulating tumor repopulation (pages 860–866). These results may have important implications for the clinical use of radiotherapy or chemotherapy to induce apoptosis in tumors.
Obesity and high blood pressure are commonly associated. A study in mice now shows that hypothalamic inflammatory pathways may be the link connecting these two disorders and a potential target to uncouple obesity-related hypertension from weight gain (pages 883–887).
A new combinatorial approach harnesses the power of immuno- and virotherapy in a vesicular stomatitis virus (VSV) vector carrying a cDNA library that expresses normal human prostate antigens, thus providing proof of principle that this vaccine can induce prostate tumor rejection in mice (pages 854–859). This strategy might bypass many of the issues associated with conventional cancer immuno- or virotherapy.
Humans with a missense mutation in LRP5 (encoding lipoprotein receptor-related protein 5) have a high bone mass phenotype, which has now been recapitulated in mice conditionally expressing this Lrp5 variant in terminally differentiated bone osteocytes (pages 684–691). These results suggest that LRP5 acts locally to increase bone mass, thereby opening avenues for new therapeutics for osteoporosis and bone injury by manipulating LRP5 signaling.
A mouse model of Joubert syndrome helps identify a crucial role for Wnt signaling in early cerebellar proliferation and midline fusion (pages 726–731). Reduced activity of this pathway causes cerebellar hypoplasia reminiscent of the cerebellar malformation observed in humans with Joubert syndrome.
Peptidoglycan recognition proteins (PGRPs) are a key part of the innate immune system's defense against bacteria. PGRPs are now shown to act through a conserved secretion stress–sensing two-component system, which leads to membrane depolarization and the release of cytotoxic hydroxyl radicals. Thus, PGRPs exploit an ancient bacterial stress response to elicit cell death, and this pathway may be targeted to produce improved antimicrobial drugs (pages 676–683).
Estrogen receptor α (ERα)-positive breast cancers often find a way to circumvent endocrine therapies such as tamoxifen. A newly described ERα kinase, lemur tyrosine kinase-3 (LMTK3), may provide both a diagnostic advance and a new therapeutic target to fight these resistant, aggressive tumors.
Some individuals with estrogen receptor–α (ER-α)-positive breast cancer do not respond to tamoxifen treatment. Increased expression of the ubiquitin ligase CUEDC2 may contribute to this endocrine resistance by reducing theamounts of ER-α (pages 708–714).
The success of organ transplantation is severely hindered by immune-mediated rejection, but the steps involved in this process remain poorly defined. A new imaging study now reveals the sequence of events and immune cells involved in graft rejection in a mouse model, providing insights into the points at which the immune system could be rationally targeted to prevent transplant rejection (pages 744–749).
Although attention deficit hyperactivity disorder (ADHD) is a highly heritable and common psychiatric disorder, few susceptibility genes have been identified. A new multidisciplinary genetic study in humans and mice reveals GIT1 (encoding G protein–coupled receptor kinase–interacting protein-1) as a previously undescribed ADHD susceptibility gene in humans and provides new insights into the underlying mechanisms of this condition (pages 566–572).
Although leukocyte activation in fat tissue promotes obesity-related insulin resistance, a role for B cells has been unclear. A new study in obese mice shows that they enter the fat tissue to activate T cell function and boost inflammation, exacerbating the metabolic disease (pages 610–617).
Interleukin-2 receptor-α (IL-2Rα) on antigen-presenting dendritic cells (DCs) is now shown to trans-present IL-2 to T cells during the earliest stages of T cell activation (604–609). The resulting T cell proliferation is blocked by daclizumab, an IL-2Rα–specific antibody used to treat multiple sclerosis and prevent transplant rejection, highlighting the importance of understanding individual variability in immune responses to daclizumab treatment.
