Immunotherapy (IO) has revolutionized the therapy landscape of non-small cell lung cancer (NSCLC), significantly prolonging the overall survival (OS) of advanced stage patients. Over the recent years IO therapy has been broadly integrated into the first-line setting of non-oncogene driven NSCLC, either in combination with chemotherapy, or in selected patients with PD-L1high expression as monotherapy. Still, a significant proportion of patients suffer from disease progression. A better understanding of resistance mechanisms depicts a central goal to avoid or overcome IO resistance and to improve patient outcome. We here review major cellular and molecular pathways within the tumor microenvironment (TME) that may impact the evolution of IO resistance. We summarize upcoming treatment options after IO resistance including novel IO targets (e.g. RIG-I, STING) as well as interesting combinational approaches such as IO combined with anti-angiogenic agents or metabolic targets (e.g. IDO-1, adenosine signaling, arginase). By discussing the fundamental mode of action of IO within the TME, we aim to understand and manage IO resistance and to seed new ideas for effective therapeutic IO concepts.

A site-directed photocrosslink approach was used to elucidate components that interact directly with ADPribosylation factor (ARF)-GTP during coat assembly. Two ARF mutants were generated that contain a photolabile amino acid at positions distant to each other within the ARF molecule. Here we show that one of the two positions specifically interacts with coatomer subunit ␤ both on Golgi membranes and in isolated coat protein complex type I (COPI)-coated vesicles. Thus, a direct and GTP-dependent interaction of coatomer via ␤-coat protein complex (COP) with ARF is involved in the coating of COPI-coated vesicles. These data implicate a bivalent interaction of the complex with the donor membrane during vesicle formation.

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A site-directed photocross-linking approach was employed to determine components that act downstream of ADP-ribosylation factor (ARF). To this end, a photolabile phenylalanine analog was incorporated at various positions of the putative effector region of the ARF molecule. Depending on the position of incorporation, we find specific and GTP-dependent interactions of ARF with two subunits of the coatomer complex, ␤-COP and ␥-COP, as well as an interaction with a cytosolic protein (ϳ185 kDa). In addition, we observe homodimer formation of ARF molecules at the Golgi membrane. These data suggest that the binding site of ARF to coatomer is at the interface of its ␤-and ␥-subunits, and this is in close proximity to the second site of interaction of coatomer with the Golgi membrane, the binding site within ␥-COP for cytosolic dibasic/diphenylalanine motifs.

RNA editing via the conversion of adenosine (A) to inosine (I) is catalyzed by two major families of adenosine deaminases acting on RNA (ADARs), ADAR1 and ADAR2. This genetic recoding process is known to play essential roles in the brain, due in part to changes in functional activities of edited neurotransmitter receptors and ion channels. Little is known, however, about the physiological regulation and function of A to I RNA editing in peripheral tissues and other biological processes. Here, we report that both ADAR1 and ADAR2 are expressed in the murine pancreatic islets, and ADAR2 is primarily localized in the islet endocrine cells. In contrast to ADAR1, ADAR2 transcripts in the pancreatic islets exhibit a nearly 2-fold increase in insulin-resistant mice chronically fed a high fat diet. Concurrent with this diet-induced metabolic stress, RNA editing in the islets is dramatically enhanced for the RNA transcripts encoding the ionotropic glutamate receptor subunit B. Moreover, ADAR2 protein expression is repressed in the islets under fuel deficiency condition during fasting, and this repression can be completely reversed by refeeding. We also show that, specifically in pancreatic ␤-cell lines, not only the expression of ADAR2 but also the glutamate receptor subunit B editing and ADAR2 self-editing are markedly augmented in response to glucose at the physiological concentration for insulin secretion stimulation. Thus, RNA editing by ADAR2 in pancreatic islets and ␤-cells is metabolically regulated by nutritional and energy status, suggesting that A to I RNA editing is most likely involved in the modulation of pancreatic islet and ␤-cell function.RNA editing through the conversion of adenosine (A) to inosine (I) within pre-mRNAs is a genetic recoding process found in a variety of organisms, including mammals (1). The search for the RNA substrates targeted for this hydrolytic deamination modification has recently revealed abundant A to I editing sites in the human transcriptome, predominantly occurring in non-coding regions of the RNA, such as Alu repeats (2). A to I editing is catalyzed by two major families of ubiquitously expressed adenosine deaminases acting on RNA (ADARs), 2 denoted ADAR1 and ADAR2 (1, 3). A to I RNA editing is known to affect a broad range of biological processes from pre-mRNA splicing to mRNA stability to coding capacity changes (4). Previously reported studies indicate that A to I RNA editing plays critical roles in the function and development of the central nervous system, due in a large part to the regulation via editing of the activities of neurotransmitter receptors and ion channels, including the ionotropic glutamate receptors (GluRs), G-protein-coupled serotonin-2C subtype receptor, and Kv1.1 potassium channel (5-10). Because inosine can be recognized as guanosine by the cellular protein translation apparatus, site-selective editing at crucial sites within the coding regions of RNA transcripts results in codon changes, and subsequently, altered functional behaviors of the encoded pro...

Background: Increasing evidence suggests that diabetes mellitus (DM) may be associated with an increased risk of bladder cancer. We performed an updated meta-analysis to examine the association between DM and risk of bladder cancer. Materials and Methods: We systematically searched the EMBASE and Medline (PubMed) databases (from inception through February 1, 2013) and reviewed the reference lists of relevant publications to search for additional studies. Summary relative risks (RRs) with 95% confidence intervals (CIs) were calculated with random-effects models. Results: In total, 10 case-control and 14 cohort studies met the inclusion criteria. Analysis of all studies showed that DM was associated with an increased risk of bladder cancer (RR 1.30, 95% CI 1.18-1.43). There was heterogeneity among studies (P heterogeneity < 0.001, I 2 = 81.5%). Cohort studies showed a lower risk (RR 1.23, 95% CI 1.09-1.37) than case-control studies (odds ratio 1.46, 95% CI 1.20-1.78). The positive association was significant only in women (RR 1.23, 95% CI 1.02-1.49), but not in men (RR 1.07, 95% CI 0.97-1.18). The combined RRs remained unchanged before and after the studies on type 1 diabetes were excluded from analysis. The association between DM and bladder cancer risk did not differ significantly by methods of DM ascertainment. The combined RRs were 1.17 (95% CI 1.03-1.34), 1.34 (95% CI 1.19-1.51), and 1.57 (95% CI 0.96-2.55), respectively, when restricting the analysis to the studies accounting for body mass index, cigarette smoking, or glucose-lowering drug use. Conclusions: This meta-analysis indicates a positive association between DM and risk of bladder cancer. Further studies are warranted to determine whether DM prevention and control can reduce risk of bladder cancer.

BackgroundType 2 diabetes mellitus (T2DM) has been suggested to increase the risk of cancers. The aim of this study was to investigate the risk of common cancers in Chinese patients with T2DM.MethodsA population-based retrospective cohort study including 36,379 T2DM patients was conducted in Minhang District of Shanghai, China, during 2004 to 2010. All T2DM patients were enrolled from the standardized management system based on local electronic information system. Newly-diagnosed cancer cases were identified by record-linkage with the Shanghai Cancer Registry. Standardized incidence ratios (SIR) and 95 % confidence interval (CI) were used to estimate the risk of cancers among T2DM patients.ResultsOverall crude incidence rate (CIR) of cancers was 955.21 per 105 person-years in men and 829.57 per 105 person-years in women. Increased risk of cancer was found in both gender, with an SIR being 1.28 (95 % CI = 1.17–1.38) in men and 1.44 (95 % CI =1.32–1.55) in women. Increased risk of colon (SIR = 1.97; 95 % CI = 1.49 to 2.46), rectum (1.72; 1.23 to 2.21), prostate (2.87; 2.19 to 3.56), and bladder cancers (1.98, 1.28 to 2.68) were observed in men and elevated risk of colon (1.67; 1.25 to 2.08), breast (1.66; 1.38 to 1.95), and corpus uteri cancers (2.87; 2.03 to 3.71) were observed in women.ConclusionsOur results indicate that Chinese patients with T2DM may have an increased risk of some cancers, and the increase may vary by sub-sites of cancers.

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