Immunotherapy is heralded as one of the most important advances in oncology. Until recently, only limited immunotherapeutic options were available in selected immunogenic cancers like melanoma and renal cell carcinomas. Nowadays, there is an improved understanding that anti-tumor immunity is controlled by a delicate balance in the tumor microenvironment between immune stimulatory and immune inhibitory pathways. Either by blocking the inhibitory pathways or stimulating the activating pathways that regulate cytotoxic lymphocytes, anti-tumor immunity can be enhanced leading to durable anti-tumor responses. Drugs which block the immune regulatory checkpoints namely the PD-1/PDL1 and CTLA 4 pathway have shown tremendous promise in a wide spectrum of solid and hematological malignancies, significantly improving overall survival in newly diagnosed and heavily pretreated patients alike. Hence there is renewed enthusiasm in the field of immune oncology with current research focused on augmenting responses to checkpoint inhibitors by combination therapy as well as studies looking at other immune modulators and adoptive T cell therapy. In this article, we highlight the key clinical advances and concepts in immunotherapy with particular emphasis on checkpoint inhibition as well as the future direction in this field.

Purpose: Recent studies have shown that 15-deoxy-Δ 12, 14 -prostaglandin J 2 (15d-PGJ 2 ), a natural ligand for peroxisome proliferator-activated receptor-γ (PPARγ), inhibits cell proliferation and induces apoptosis. The specific molecular mechanisms underlying this effect remain to be elucidated. We examined whether 15d-PGJ 2 has antitumor activity in vitro and in vivo, and investigated the underlying mechanism. Experimental Design: We examined 15d-PGJ 2 -induced apoptosis in human leukemia cells in the context of mitochondrial injury, oxidative damage, and signaling pathway disturbances. In addition, we investigated the antitumor effect of 15d-PGJ 2 in a mouse CT-26 s.c. tumor model and HL-60 leukemia xenograft model. Results: 15d-PGJ 2 induced apoptosis in leukemia and colorectal cancer cells in a dosedependent manner and led to generation of reactive oxygen species (ROS) through mitochondria and NADPH oxidase activation, activation of JNK, and inactivation of Akt, a serine/threonine-specific protein kinase. Constitutive activation of Akt for an engineered myristoylated protein prevented 15d-PGJ 2 -mediated apoptosis but not ROS generation. Collectively, these findings suggest a hierarchical model of apoptosis induced by 15d-PGJ 2 in human leukemia cells: oxidative injury represents a primary event resulting in Akt inactivation, which in turn leads to mitochondrial injury and apoptosis. Moreover The peroxisome proliferator-activated receptor-γ (PPARγ) is a transcription factor belonging to the nuclear receptor superfamily (1, 2) and is expressed in some myeloid leukemic cell lines (3). PPARγ agonists include the natural ligands 15-deoxy-Δ 12,14 -prostaglandin J 2 (15d-PGJ 2 ; refs. 4, 5) and lysophosphatidic acid (6), and the synthetic thiazolidinedione class of antidiabetic drugs such as ciglitazone (7). The cyclopentenone PG 15d-PGJ 2 is a product of the cyclooxygenase pathway and is the final metabolite of PGD 2 (8). 15d-PGJ 2 has highly reactive structures that contain an α, β-unsaturated ketone susceptible to nucleophilic addition reactions. For example, the cyclopentenone ring of 15d-PGJ 2 covalently modifies cellular proteins such as the p65 and p50 subunits of NF-κB (9, 10). The potent antiproliferative and antiviral effects of cyclopentenone PGs are attributed to this reactivity (11).15d-PGJ 2 has recently received attention because it functions as a potential regulator of diverse processes, including cell growth, differentiation, and inflammation. It also exerts antitumorigenic activity; for example, 15d-PGJ 2 activation of PPARγ significantly inhibits cell growth and induces apoptosis in several types of cancer cells (12)(13)(14)(15). Some effects of 15d-PGJ 2 are exerted through its interaction with PPARγ (4, 5); however, more recent evidence indicates that 15d-PGJ 2 can also act independently of PPARγ (16). Until now, the molecular mechanism of the antineoplastic activity of 15d-PGJ 2 has not been fully elucidated. In addition, controversial data on the role of PPARγ in colon cancer sugg...

The purpose of this study was to examine human papillomavirus (HPV) knowledge and vaccine acceptability in a convenience sample of immigrant Hispanic men, many of whom are parents of adolescents. Data on 189 male callers were collected from the National Cancer Institute’s Cancer Information Service Spanish-language call center. Most participants were willing to vaccinate their adolescent son (87.5 %) or daughter (78.8 %) against HPV. However, among this sample, awareness of HPV was low and knowledge of key risk factors varied. These findings can help guide the development of culturally informed educational efforts aimed at increasing informed decision-making about HPV vaccination among Hispanic fathers.

a b s t r a c tFrondoside A is a pentaoside having an acetyl moiety at the aglycon ring and xylose as a third monosaccharide residue. Cucumarioside A 2 -2 is a pentaoside having glucose as a third monosaccahride unit. We compared the effects of frondoside A and A 2 -2 for cell death-inducing capability with close attention paid to structure-activity relationships. Both frondoside A and A 2 -2 strongly induced apoptosis of leukemic cells. Frondoside A-induced apoptosis was more potent and rapid than A 2 -2-induced apoptosis. A 2 -2-induced but not frondoside A-induced apoptosis was caspase-dependent. This suggests that holothurians may induce apoptosis of leukemic cells caspase-dependently or -independently, depending on the holothurian structure.

Combination treatment with MnTnHex-2-PyP and IR substantially reduced cell viability, clonogenic cell survival, and DNA damage repair and synergistically increased IR-induced apoptosis of 4T1 and B16 cells. MnTnHex-2-PyP in combination with IR caused a significant delay in growth of 4T1 and B16 xenograft tumors. MnTnHex-2-PyP dose-dependently enhanced IR-mediated production of HO-derived species, but not superoxide. Catalase overexpression reversed MnTnHex-2-PyP-enhanced ROS production and apoptosis. Demonstrated suppression of phosphorylation of several mitogen-activated protein (MAP) kinases and activation of NF-κB by MnTnHex-2-PyP/IR, which presumably inhibited activation of the antiapoptotic pathway, are in agreement with our other data on the apoptosis of cancer cells. Innovation and Conclusions: MnTnHex-2-PyP exerted a radiosensitizing effect on 4T1 and B16 tumor models in vitro and in vivo via pro-oxidative actions and therefore bears a large therapeutic potential. When combined with IR, it attenuated DNA damage repair and triggered a shift from prosurvival pathways to apoptotic cell death, likely due to increased ROS production and disturbed cellular redox balance, acting at the level of nuclear factor κB (NF-κB). Antioxid. Redox Signal. 27, 1067-1082.

Extracellular signal-regulated kinase 1 (ERK1) and ERK2 signaling in the spinal cord dorsal horn (SCDH) has been implicated in injuryinduced pain hypersensitivity. Available ERK pathway inhibitors cannot distinguish between ERK1 and ERK2, nor can they differentially target the expression of neuronal or glial ERK1/2. We selectively inhibited the expression of ERK2 in neurons of the adult mouse SCDH by use of an ERK2 small interfering RNA (siRNA) delivered by a neurotropic adenoassociated viral vector. In situ hybridization revealed a siRNA vector-induced decrease in ERK2 mRNA in the ipsilateral SCDH. Immunohistochemistry showed a decreased neuronal phospho-ERK1/2 (pERK1/2), and Western blot analysis revealed that both ERK2 expression and phosphorylation were reduced by the siRNA vector. In contrast, basal ERK1 expression was not affected, although pERK1 was slightly increased. The siRNA vector-induced knockdown of ERK2 expression in the SCDH did not alter the baseline mechanical or thermal paw withdrawal thresholds. Hindpaw intraplantar injection of complete Freund's adjuvant (CFA) produced peripheral inflammation, mechanical allodynia, and thermal hyperalgesia in vector control animals that persisted for at least 96 h. It also caused an increase in SCDH ERK1 and ERK2 levels at 96 h and pERK1 and pERK2 levels at 1 and 96 h. The ERK2 siRNA vector prevented changes in ERK1, ERK2, and pERK2. In addition, the siRNA vector protected the animals from developing mechanical allodynia and thermal hyperalgesia throughout the 96 h after CFA. These findings indicate that ERK2 in the SCDH neurons is critical for the development of inflammatory pain hypersensitivity.

This article addresses the challenges that non-native English-speaking teacher trainees face as they begin teaching English as a Second Language (ESL) in Western, English-speaking countries. Despite a great deal of training, non-native speaker teachers may be viewed as inadequate language teachers because they often lack native speaker competence in the target language and culture. However, non-native speaker teachers possess distinct advantages over native speakers including a deeper understanding of learners' first languages and an ability to explain second language features in ways that students can understand. This article explores the linguistic and pedagogical skills that are required for teaching ESL to immigrant students in primary and secondary schools. It concludes that while it is important for non-native teachers to continuously strive to attain high levels of written and oral proficiencies in English, they must also become familiar with the discourse and cultures of the schools and communities in which they work. In addition, non-native teacher candidates need to be trained to become ethnographers of their own and others' interactions and draw on the knowledge about the different ways of learning and using language to grow as teachers and professionals. This article provides specific suggestions for teacher education programs to better prepare nonnative teachers to meet these challenges.

Following peripheral inflammation, NMDA receptor (NMDAR) activation in spinal cord dorsal horn neurons facilitates the generation of pain in response to low threshold inputs (allodynia) and signals the phosphorylation of protein kinase C (pPKC) and extracellular signal-regulated kinase 2 (pERK2). Intraplantar complete Freund's adjuvant (CFA) induces inflammatory nociception (allodynic pain) at 24 hours (h) with a concurrent increase in neuronal pPKCgamma and pERK2 but not glial pERK2. These effects are attenuated in a spatial knockout of the NMDAR (NR1 KO) confined to SCDH neurons. Although glia and proinflammatory cytokines are implicated in the maintenance of inflammatory pain and neuronal activation, the role of NMDARs and neuronal-glial-cytokine interactions that initiate and maintain inflammatory pain are not well defined. In the maintenance phase of inflammatory pain at 96h after CFA the NR1 KO mice are no longer protected from allodynia and the SCDH expression of pPKCgamma and pERK2 are increased. At 96h the expression of the proinflammatory cytokine, IL-1beta, and pERK2 are increased in astrocytes. Intrathecal IL-1 receptor antagonist (IL-1ra), acting on neuronal IL-1 receptors, completely reverses the allodynia at 96h after CFA. Deletion of NMDAR-dependent signaling in neurons protects against early CFA-induced allodynia. Subsequent NMDAR-independent signaling that involves neuronal expression of pPKCgamma and the induction of pERK2 and IL-1beta in activated astrocytes contributes to the emergence of NMDAR-independent inflammatory pain behavior at 96h after CFA. Effective reduction of the initiation and maintenance of inflammatory pain requires targeting the neuron-astrocyte-cytokine interactions revealed in these studies.