A Sub-Type of Familial Pancreatic Cancer: Evidence and Implications of Loss-of-Function Polymorphisms in Indoleamine-2,3-Dioxygenase-2.

BACKGROUND: Variation in an individual\u27s genetic status can impact the development of pancreatic ductal adenocarcinoma; however, the majority of familial pancreatic cancers (FPC) cannot yet be attributed to a specific inherited mutation. We present data suggesting a correlation between loss-of-function single nucleotide polymorphisms (SNPs) in an immune regulator gene, indoleamine-2,3-dioxygenase-2 (IDO2), and an increased risk of FPC. STUDY DESIGN: Germline DNA from patients who underwent resection for pancreatic ductal adenocarcinoma (n = 79) was sequenced for the IDO2 SNPs R248W and Y359Stop. Genotypes resulting in inactivation of IDO2 (Y325X homozygous, R248W homozygous) were labeled as homozygous, and the other genotypes were grouped as wild-type or heterozygous. Genotype distributions of each SNP were analyzed for Hardy-Weinberg deviation. A genotype frequency set from the 1000 Genomes Project (n = 99) was used as a genetic control for genotype distribution comparisons. RESULTS: A significant 2-fold increase in the overall prevalence of the Y359Stop homozygous genotype compared with the expected Hardy-Weinberg equilibrium was noted (p \u3c 0.05). Familial pancreatic cancer was noted in 15 cases (19%) and comparison of the FPC cohort set to the genetic control set showed a 3-fold increase in Y359Stop homozygous rates (p = 0.054). Overall in our cohort, the homozygous genotype group was associated with increased risk of FPC (odds ratio 5.4; 95% CI 1.6 to 17.6; p \u3c 0.01). Sex, age at diagnosis, and history of tobacco use were not found to be significantly associated with FPC. CONCLUSIONS: Our preliminary data suggest a strong association between the IDO2 inactivating Y359Stop SNP and an increased risk of FPC when compared with the control group. Future studies will evaluate the value of IDO2 genotyping as a prognostic, early detection marker for pancreatic ductal adenocarcinoma and a predictive marker for novel immune checkpoint therapies

Posttranscriptional Upregulation of IDH1 by HuR Establishes a Powerful Survival Phenotype in Pancreatic Cancer Cells.

Cancer aggressiveness may result from the selective pressure of a harsh nutrient-deprived microenvironment. Here we illustrate how such conditions promote chemotherapy resistance in pancreatic ductal adenocarcinoma (PDAC). Glucose or glutamine withdrawal resulted in a 5- to 10-fold protective effect with chemotherapy treatment. PDAC xenografts were less sensitive to gemcitabine in hypoglycemic mice compared with hyperglycemic mice. Consistent with this observation, patients receiving adjuvant gemcitabine (n = 107) with elevated serum glucose levels (HgbA1C \u3e 6.5%) exhibited improved survival. We identified enhanced antioxidant defense as a driver of chemoresistance in this setting. ROS levels were doubled in vitro by either nutrient withdrawal or gemcitabine treatment, but depriving PDAC cells of nutrients before gemcitabine treatment attenuated this effect. Mechanistic investigations based on RNAi or CRISPR approaches implicated the RNA binding protein HuR in preserving survival under nutrient withdrawal, with or without gemcitabine. Notably, RNA deep sequencing and functional analyses in HuR-deficient PDAC cell lines identified isocitrate dehydrogenase 1 (IDH1) as the sole antioxidant enzyme under HuR regulation. HuR-deficient PDAC cells lacked the ability to engraft successfully in immunocompromised mice, but IDH1 overexpression in these cells was sufficient to fully restore chemoresistance under low nutrient conditions. Overall, our findings highlight the HuR–IDH1 regulatory axis as a critical, actionable therapeutic target in pancreatic cancer

Separation of Diastereomers, Structural Isomers, and Homologs of n5 -Cyclopentadienyl Cobalt and Dinuclear Molybdenum Complexes by Reverse Phase High Performance Liquid Chromatography Using Deoxygenated Solvents

High Performance Liquid Chromatography (HPLC) is being used as an analytical and preparative tool for the characterization and isolation of a series of air-sensitive organometallic compounds, Reverse phase chranatography with octadecylsilyl-modified silica (ODS) as a stationary phase and polar mobile phases saturated with argon are employed in the separation of products

How common is truly benign MS in a UK population?

Objectives The prevalence and definition of benign multiple sclerosis (BMS) remain controversial. Most definitions are based on the Expanded Disability Status Scale (EDSS), not encompassing the wider impact of disease. The explanation for favourable outcomes remains unclear. We aim to provide a detailed characterisation of patients with low EDSS scores at long disease durations. Methods We screened a population-based registry containing 3062 people with MS to identify individuals with unlimited walking ability at disease durations >15 years. A representative cohort underwent detailed clinical assessment and classified as having BMS according to EDSS score <3, no significant fatigue, mood disturbance, cognitive impairment or disrupted employment, and had not received a disease-modifying therapy. We determined patient-reported perceptions of MS status and made comparisons with EDSS-based definitions. Results Of 1049 patients with disease duration of >15 years, 200 (19.1%) had most recent EDSS score <4.0. Detailed contemporary clinical assessment of a representative sample of 60 of these patients revealed 48 (80%) had an EDSS score of <4.0, 35 (58%) <3.0 and 16 (27%) <2.0. Only nine (15%) fulfilled our criteria for BMS; impaired cognition (57%) and effects on employment (52%) the most common causes for exclusion. Meanwhile, 33/60 (69%) patients considered their disease benign. Population frequency for BMS was estimated at 2.9% (95% CI 2.0 to 4.1). Conclusions Comprehensive assessment reveals a small minority of people with MS who appear genuinely benign after 15 years. Study of such individuals may uncover insights about disease pathogenesis. However, discrepancy between patient perception and clinician perception of BMS undermines use of the term ‘benign’ in clinical settings

Effects of confinement and surface enhancement on superconductivity

Within the Ginzburg-Landau approach a theoretical study is performed of the effects of confinement on the transition to superconductivity for type-I and type-II materials with surface enhancement. The superconducting order parameter is characterized by a negative surface extrapolation length $b$. This leads to an increase of the critical field $H_{c3}$ and to a surface critical temperature in zero field, $T_{cs}$, which exceeds the bulk $T_c$. When the sample is {\em mesoscopic} of linear size $L$ the surface induces superconductivity in the interior for $T T_{cs}$. In analogy with adsorbed fluids, superconductivity in thin films of type-I materials is akin to {\em capillary condensation} and competes with the interface delocalization or "wetting" transition. The finite-size scaling properties of capillary condensation in superconductors are scrutinized in the limit that the ratio of magnetic penetration depth to superconducting coherence length, $\kappa \equiv \lambda/\xi$, goes to zero, using analytic calculations. While standard finite-size scaling holds for the transition in non-zero magnetic field $H$, an anomalous critical-point shift is found for H=0. The increase of $T_c$ for H=0 is calculated for mesoscopic films, cylindrical wires, and spherical grains of type-I and type-II materials. Surface curvature is shown to induce a significant increase of $T_c$, characterized by a shift $T_c(R)-T_c(\infty)$ inversely proportional to the radius $R$.Comment: 37 pages, 5 figures, accepted for PR

Citostatsko i protuupalno djelovanje polisaharida biljke Ganoderma lucidum

In this study, polysaccharides were isolated from Ganoderma lucidum (Polyporaceae) and their antitumor and anti-inflammatory activities were investigated using in vivo models. Potential antitumor activity was shown by G. lucidum polysaccharides (GLP) against solid tumor induced by Ehrlich’s ascites carcinoma cells. GLP at 100 mg kg–1 body mass showed 80.8 and 77.6 % reduction in tumour volume and tumour mass, respectively, when administered 24 h after tumour implantation. Again, GLP at the same dose but when administered prior to tumour inoculation, showed 79.5 and 81.2 % inhibition of tumour volume and tumour mass, respectively. GLP showed significant dose-dependent activity in carrageenean-induced (acute) and formalin-induced (chronic) inflammation assays. At 100 mg kg–1, GLP exhibited 57.6 and 58.2 % inhibition in carrageenean-induced and formalin-induced assays, respectively.U radu je ispitano in vivo citostatsko i protuupalno djelovanje polisaharida (GLP) izoliranih iz biljke Ganoderma lucidum (Polyporaceae). Ispitivani polisaharidi pokazali su potencijalno antitumorsko djelovanje na Ehrlichov ascitesni tumor. GLP su u dozi od 100 mg kg1 tjelesne mase inhibirali volumen tumora za 80,8, a njegovu masu za 77,6 %, kada su primijenjeni 24 h nakon implantacije tumora. Ako se GLP daju u istoj dozi prije inokulacije tumora, inhibiraju volumen tumora za 79,5, a njegovu masu za 81,2 %. GLP pokazuju značajno, o dozi ovisno, protuupalno djelovanje u karagenan testu (akutna upala) i formalin testu (kronična upala). U dozi od 100 mg kg1, GLP inhibiraju upalne procese za 57,6 odnosno 58,2 % u testu s karagenanom, odnosno formalinom

Citostatsko i protuupalno djelovanje polisaharida biljke Ganoderma lucidum

In this study, polysaccharides were isolated from Ganoderma lucidum (Polyporaceae) and their antitumor and anti-inflammatory activities were investigated using in vivo models. Potential antitumor activity was shown by G. lucidum polysaccharides (GLP) against solid tumor induced by Ehrlich’s ascites carcinoma cells. GLP at 100 mg kg–1 body mass showed 80.8 and 77.6 % reduction in tumour volume and tumour mass, respectively, when administered 24 h after tumour implantation. Again, GLP at the same dose but when administered prior to tumour inoculation, showed 79.5 and 81.2 % inhibition of tumour volume and tumour mass, respectively. GLP showed significant dose-dependent activity in carrageenean-induced (acute) and formalin-induced (chronic) inflammation assays. At 100 mg kg–1, GLP exhibited 57.6 and 58.2 % inhibition in carrageenean-induced and formalin-induced assays, respectively.U radu je ispitano in vivo citostatsko i protuupalno djelovanje polisaharida (GLP) izoliranih iz biljke Ganoderma lucidum (Polyporaceae). Ispitivani polisaharidi pokazali su potencijalno antitumorsko djelovanje na Ehrlichov ascitesni tumor. GLP su u dozi od 100 mg kg1 tjelesne mase inhibirali volumen tumora za 80,8, a njegovu masu za 77,6 %, kada su primijenjeni 24 h nakon implantacije tumora. Ako se GLP daju u istoj dozi prije inokulacije tumora, inhibiraju volumen tumora za 79,5, a njegovu masu za 81,2 %. GLP pokazuju značajno, o dozi ovisno, protuupalno djelovanje u karagenan testu (akutna upala) i formalin testu (kronična upala). U dozi od 100 mg kg1, GLP inhibiraju upalne procese za 57,6 odnosno 58,2 % u testu s karagenanom, odnosno formalinom

LEMUR: Large European Module for solar Ultraviolet Research. European contribution to JAXA's Solar-C mission

Understanding the solar outer atmosphere requires concerted, simultaneous solar observations from the visible to the vacuum ultraviolet (VUV) and soft X-rays, at high spatial resolution (between 0.1" and 0.3"), at high temporal resolution (on the order of 10 s, i.e., the time scale of chromospheric dynamics), with a wide temperature coverage (0.01 MK to 20 MK, from the chromosphere to the flaring corona), and the capability of measuring magnetic fields through spectropolarimetry at visible and near-infrared wavelengths. Simultaneous spectroscopic measurements sampling the entire temperature range are particularly important. These requirements are fulfilled by the Japanese Solar-C mission (Plan B), composed of a spacecraft in a geosynchronous orbit with a payload providing a significant improvement of imaging and spectropolarimetric capabilities in the UV, visible, and near-infrared with respect to what is available today and foreseen in the near future. The Large European Module for solar Ultraviolet Research (LEMUR), described in this paper, is a large VUV telescope feeding a scientific payload of high-resolution imaging spectrographs and cameras. LEMUR consists of two major components: a VUV solar telescope with a 30 cm diameter mirror and a focal length of 3.6 m, and a focal-plane package composed of VUV spectrometers covering six carefully chosen wavelength ranges between 17 and 127 nm. The LEMUR slit covers 280" on the Sun with 0.14" per pixel sampling. In addition, LEMUR is capable of measuring mass flows velocities (line shifts) down to 2 km/s or better. LEMUR has been proposed to ESA as the European contribution to the Solar C mission.Comment: 35 pages, 14 figures. To appear on Experimental Astronom

pp32 (ANP32A) Expression Inhibits Pancreatic Cancer Cell Growth and Induces Gemcitabine Resistance by Disrupting HuR Binding to mRNAs

The expression of protein phosphatase 32 (PP32, ANP32A) is low in poorly differentiated pancreatic cancers and is linked to the levels of HuR (ELAV1), a predictive marker for gemcitabine response. In pancreatic cancer cells, exogenous overexpression of pp32 inhibited cell growth, supporting its long-recognized role as a tumor suppressor in pancreatic cancer. In chemotherapeutic sensitivity screening assays, cells overexpressing pp32 were selectively resistant to the nucleoside analogs gemcitabine and cytarabine (ARA-C), but were sensitized to 5-fluorouracil; conversely, silencing pp32 in pancreatic cancer cells enhanced gemcitabine sensitivity. The cytoplasmic levels of pp32 increased after cancer cells are treated with certain stressors, including gemcitabine. pp32 overexpression reduced the association of HuR with the mRNA encoding the gemcitabine-metabolizing enzyme deoxycytidine kinase (dCK), causing a significant reduction in dCK protein levels. Similarly, ectopic pp32 expression caused a reduction in HuR binding of mRNAs encoding tumor-promoting proteins (e.g., VEGF and HuR), while silencing pp32 dramatically enhanced the binding of these mRNA targets. Low pp32 nuclear expression correlated with high-grade tumors and the presence of lymph node metastasis, as compared to patients' tumors with high nuclear pp32 expression. Although pp32 expression levels did not enhance the predictive power of cytoplasmic HuR status, nuclear pp32 levels and cytoplasmic HuR levels associated significantly in patient samples. Thus, we provide novel evidence that the tumor suppressor function of pp32 can be attributed to its ability to disrupt HuR binding to target mRNAs encoding key proteins for cancer cell survival and drug efficacy