Carolingian Commentaries on the Apocalypse by Theodulf and Smaragdus

In the early ninth-century Theodulf of Orleans and Smaragdus of Saint Mihiel served as advisers to Charlemagne. This book provides English translations of a Latin commentary on the Apocalypse written by Theodulf and three homilies on the Apocalypse by Smaragdus. A comprehensive essay introduces these texts, their authors, sources, and place in ninth-century biblical exegesis.https://scholarworks.wmich.edu/mip_teamscs/1001/thumbnail.jp

The Seven Seals of the Apocalypse: Medieval Texts in Translation

Filling today\u27s religious book market are Apocalypse commentaries teaching that the seven seals of Revelation 5–8 describe tragedies that are to take place in the last days. Medieval Europeans, on the other hand, thought very differently about the seven seals. Some used the seven seals for catechetical purposes and associated them with seven major events in the life of Christ or seven gifts of the Holy Spirit. Other medieval writers taught that the seven seals contained symbols about life in the church between the first and second comings of Christ. Still others viewed the seals as milestones in the grand outline of salvation history. This book illustrates this vastness of medieval interpretive tradition on the seven seals. It includes fifteen texts from the sixth through the fifteenth centuries, which have been organized under three headings: those illustrating christological interpretations of the seven seals, those proposing ecclesiastical interpretations, and those giving historical interpretations.https://scholarworks.wmich.edu/mip_teamscs/1008/thumbnail.jp

Early Latin Commentaries on the Apocalypse

Many commentaries on the Apocalypse were produced in the early Middle Ages. This book provides translations of two Apocalypse commentaries from the seventh and eighth centuries. On the Mysteries of the Apocalypse of John is part of a large one-volume Reference Bible composed about 750. Written probably by an Irish teacher residing in northern France, it answers difficulties arising from the biblical text. The Handbook on the Apocalypse of the Apostle John, attributed erroneously to Jerome and written before 767, contains brief moral and allegorical interpretations of particular words and phrases of the Apocalypse. The introduction highlights the unique features of each commentary and the interrelationship of the three texts.https://scholarworks.wmich.edu/mip_teamscs/1007/thumbnail.jp

Glycogen synthesis correlates with androgen-dependent growth arrest in prostate cancer

BACKGROUND: Androgen withdrawal in normal prostate or androgen-dependent prostate cancer is associated with the downregulation of several glycolytic enzymes and with reduced glucose uptake. Although glycogen metabolism is known to regulate the intracellular glucose level its involvement in androgen response has not been studied. METHODS: We investigated the effects of androgen on glycogen phosphorylase (GP), glycogen synthase (GS) and on glycogen accumulation in the androgen-receptor (AR) reconstituted PC3 cell line containing either an empty vector (PC3-AR-V) or vector with HPV-E7 (PC3-AR-E7) and the LNCaP cell line. RESULTS: Androgen addition in PC3 cells expressing the AR mimics androgen ablation in androgen-dependent prostate cells. Incubation of PC3-AR-V or PC3-AR-E7 cells with the androgen R1881 induced G1 cell cycle arrest within 24 hours and resulted in a gradual cell number reduction over 5 days thereafter, which was accompanied by a 2 to 5 fold increase in glycogen content. 24 hours after androgen-treatment the level of Glucose-6-P (G-6-P) had increased threefold and after 48 hours the GS and GP activities increased twofold. Under this condition inhibition of glycogenolysis with the selective GP inhibitor CP-91149 enhanced the increase in glycogen content and further reduced the cell number. The androgen-dependent LNCaP cells that endogenously express AR responded to androgen withdrawal with growth arrest and increased glycogen content. CP-91149 further increased glycogen content and caused a reduction of cell number. CONCLUSION: Increased glycogenesis is part of the androgen receptor-mediated cellular response and blockage of glycogenolysis by the GP inhibitor CP-91149 further increased glycogenesis. The combined use of a GP inhibitor with hormone therapy may increase the efficacy of hormone treatment by decreasing the survival of prostate cancer cells and thereby reducing the chance of cancer recurrence

Use of Anticoagulant Rodenticides in Single-Family Neighborhoods Along an Urban-Wildland Interface in California

Urbanization poses many threats for many wildlife species. In addition to habitat loss and fragmentation, non-target wildlife species are vulnerable to poisoning by rodenticides, especially acutely toxic second generation anticoagulant rodenticides (SGARs). Although such poisonings are well documented for birds and mammals worldwide, the pathways by which these widely available compounds reach non-target wildlife have not been adequately studied, particularly in urban landscapes. Long-term studies of wild carnivores in and around Santa Monica Mountains National Recreation Area, a national park north of Los Angeles, have documented \u3e85% exposure to anticoagulant rodenticides among bobcats, coyotes, and mountain lions. To investigate potential mechanisms of transfer of chemicals from residential users of rodenticides to non-target wildlife in the Santa Monica Mountains in Los Angeles County, California, we distributed surveys to residents in two study areas on the north (San Fernando Valley) and south (Bel Air-Hollywood Hills) slopes of these mountains. We assessed knowledge of residents about the environmental effects of rodenticides, and for information about individual application of chemicals. We asked for the same information from pest control operators (PCOs) in both study areas. Forty residents completed the survey in the San Fernando Valley area, and 20 residents completed the survey in Bel Air-Hollywood Hills. Despite the small number of total responses, we documented a number of important findings. Homeowners (as opposed to gardeners or PCOs) were the primary applicators of rodenticides, predominantly SGARs, and awareness of the hazards of secondary poisoning to wildlife was not consistent. Some residents reported improperly applying rodenticides (e.g., exceeding prescribed distances from structures), and in one instance a respondent reported observing dead animals outside after placing poison inside a structure. Improper application of SGARs that ignores label guidelines occurs in neighborhoods along the urban–wildland interface, thereby providing a transmission pathway for chemical rodenticides to reach native wildlife. Moreover, the responses suggest that even on-label use (e.g. placing poisons inside) can create risk for non-target wildlife

Lung adenocarcinoma: Sustained subtyping with immunohistochemistry and EGFR, HER2 and KRAS mutational status

Pulmonary adenocarcinomas are still in the process of achieving morphological, immunohistochemical and genetic standardization. The ATS/ERS/IASLC proposed classification for lung adenocarcinomas supports the value of the identification of histological patterns, specifically in biopsies. Thirty pulmonary adenocarcinomas were subjected to immunohistochemical study (CK7, CK5, 6, 18, CK20, TTF1, CD56, HER2, EGFR and Ki-67), FISH and PCR followed by sequencing and fragment analysis for EGFR, HER2 and KRAS. Solid pattern showed lower TTF1 and higher Ki-67 expression. TTF1 expression was higher in non-mucinous lepidic and micropapillary patterns when compared to acinar and solid and acinar, solid and mucinous respectively. Higher Ki67 expression was present in lepidic and solid patterns compared to mucinous. EGFR membranous staining had increasing expression from non-mucinous lepidic/BA pattern to solid pattern and micropapillary until acinar pattern. EGFR mutations, mainly in exon 19, were more frequent in females, together with non-smoking status, while KRAS exon 2 mutations were statistically more frequent in males, especially in solid pattern. FISH EGFR copy was correlated gross, with mutations. HER2 copy number was raised in female tumours without mutations, in all cases. Although EGFR and KRAS mutations are generally considered mutually exclusive, in rare cases they can coexist as it happened in one of this series, and was represented in acinar pattern with rates of 42.9% and 17.9%, respectively. EGFR mutations were more frequent in lepidic/BA and acinar patterns. Some cases showed different EGFR mutations. The differences identified between the adenocarcinoma patterns reinforce the need to carefully identify the patterns present, with implications in diagnosis and in pathogenic understanding. EGFR and KRAS mutational status can be determined in biopsies representing bronchial pulmonary carcinomas because when a mutation is present it is generally present in all the histological patterns.info:eu-repo/semantics/publishedVersio

Bortezomib/docetaxel combination therapy in patients with anthracycline-pretreated advanced/metastatic breast cancer: a phase I/II dose-escalation study

The aim of this study was to determine the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of bortezomib plus docetaxel in patients with anthracycline-pretreated advanced/metastatic breast cancer. Forty-eight patients received up to eight 21-day cycles of docetaxel (60–100 mg m−2 on day 1) plus bortezomib (1.0–1.5 mg m−2 on days 1, 4, 8, and 11). Pharmacodynamic and pharmacokinetic analyses were performed in a subset of patients. Five patients experienced DLTs: grade 3 bone pain (n=1) and febrile neutropenia (n=4). The MTD was bortezomib 1.5 mg m−2 plus docetaxel 75 mg m−2. All 48 patients were assessable for safety and efficacy. The most common adverse events were diarrhoea, nausea, alopecia, asthenia, and vomiting. The most common grade 3/4 toxicities were neutropenia (44%), and febrile neutropenia and diarrhoea (each 19%). Overall patient response rate was 29%. Median time to progression was 5.4 months. In patients with confirmed response, median time to response was 1.3 months and median duration of response was 3.2 months. At the MTD, response rate was 38%. Pharmacokinetic characteristics of bortezomib/docetaxel were comparable with single-agent data. Addition of docetaxel appeared not to affect bortezomib inhibition of 20S proteasome activity. Mean alpha-1 acid glycoprotein concentrations increased from baseline at nearly all time points across different bortezomib dose levels. Bortezomib plus docetaxel is an active combination for anthracycline-pretreated advanced/metastatic breast cancer. The safety profile is manageable and consistent with the side effects of the individual agents

Reduced expression of p27 is a novel mechanism of docetaxel resistance in breast cancer cells

INTRODUCTION: Docetaxel is one of the most effective chemotherapeutic agents in the treatment of breast cancer. Breast cancers can have an inherent or acquired resistance to docetaxel but the causes of this resistance remain unclear. However, apoptosis and cell cycle regulation are key mechanisms by which most chemotherapeutic agents exert their cytotoxic effects. METHODS: We created two docetaxel-resistant human breast cancer cell lines (MCF-7 and MDA-MB-231) and performed cDNA microarray analysis to identify candidate genes associated with docetaxel resistance. Gene expression changes were validated at the RNA and protein levels by reverse transcription PCR and western analysis, respectively. RESULTS: Gene expression cDNA microarray analysis demonstrated reduced p27 expression in docetaxel-resistant breast cancer cells. Although p27 mRNA expression was found to be reduced only in MCF-7 docetaxel-resistant sublines (2.47-fold), reduced expression of p27 protein was noted in both MCF-7 and MDA-MB-231 docetaxel-resistant breast cancer cells (2.83-fold and 3.80-fold, respectively). CONCLUSIONS: This study demonstrates that reduced expression of p27 is associated with acquired resistance to docetaxel in breast cancer cells. An understanding of the genes that are involved in resistance to chemotherapy may allow further development in modulating drug resistance, and may permit selection of those patients who are most likely to benefit from such therapies

Loss of heterozygosity (LOH), malignancy grade and clonality in microdissected prostate cancer

The aim of the present study was to find out whether increasing malignancy of prostate carcinoma correlates with an overall increase of loss of heterozygosity (LOH), and whether LOH typing of microdissected tumour areas can help to distinguish between multifocal or clonal tumour development. In 47 carcinomas analysed at 25 chromosomal loci, the overall LOH rate was found to be significantly lower in grade 1 areas (2.2%) compared with grade 2 (9.4%) and grade 3 areas (8.3%, P = 0.007). A similar tendency was found for the mean fractional allele loss (FAL, 0.043 for grade 1, 0.2 for grade 2 and 0.23 for grade 3, P = 0.0004). Of 20 tumours (65%) with LOH in several microdissected areas, 13 had identical losses at 1–4 loci within two or three areas, suggesting clonal development of these areas. Markers near RB, DCC, BBC1, TP53 and at D13S325 (13q21–22) showed higher loss rates in grades 2 and 3 (between 25% and 44.4%) compared with grade 1 (0–6.6%). Tumour-suppressor genes (TSGs) near these loci might, thus, be important for tumour progression. TP53 mutations were detected in 27%, but BBC1 mutations in only 7%, of samples with LOH. Evaluation of all 25 loci in every tumour made evident that each prostate cancer has its own pattern of allelic losses. © 1999 Cancer Research Campaig