Cdc7 is a potent anti-cancer target in pancreatic cancer due to abrogation of the DNA origin activation checkpoint.

PURPOSE: Cdc7 is a serine/threonine kinase which is responsible for the 'firing' of replication origins leading to initiation of DNA replication. Inhibition or depletion of Cdc7 in normal cells triggers a DNA origin activation checkpoint causing a reversible G1 arrest. Here we investigate Cdc7 as a novel therapeutic target in pancreatic cancer. EXPERIMENTAL DESIGN: Cdc7 target validation was performed by immunoexpression profiling in a cohort of 73 patients with pancreatic adenocarcinoma including 24 controls. Secondly Cdc7 kinase was targeted in Capan-1 and PANC-1 pancreatic cancer cell line models using either an siRNA against Cdc7 or alternatively a small molecule inhibitor (SMI) of Cdc7 (PHA-767491). RESULTS: Cdc7 was significantly overexpressed in pancreatic adenocarcinoma compared to benign pancreatic tissue (median LI 34.3% vs. 1.3%; P<0.0001). Cdc7 knockdown using siRNA in Capan-1 and PANC-1 cells resulted in marked apoptotic cell death when compared with control cells. A prominent sub-G1 peak was seen on flow cytometry (sub-G1 51% vs. 3% and 45% vs. 0.7% in Capan-1 and PANC-1 cells, respectively). Annexin V labelling confirmed apoptosis in 64% vs. 11% and 75% vs. 8%, respectively. Western blotting showed cleavage of PARP-1 and caspase-3 and presence of γH2A.X. TUNEL assay showed strong staining in treated cells. These results were mirrored following Cdc7 kinase inhibition with PHA-767491. CONCLUSIONS: Our findings show that Cdc7 is a potent anti-cancer target in pancreatic adenocarcinoma and that Cdc7 immunoexpression levels might be used as a companion diagnostic to predict response to therapeutic siRNAs or SMIs directed against this kinase

Pain in veterans of the Gulf War of 1991: a systematic review

BACKGROUND: Veterans of the Persian Gulf War of 1991 have reported a range of adverse health symptoms. This systematic review aims to identify all studies that have compared the prevalence of symptoms of pain in veterans of the Gulf War to that in a non-Gulf military comparison group, and to determine whether Gulf War veterans are at increased risk of reporting pain. METHODS: Studies published between January 1990 and May 2004 were identified by searching a large number of electronic databases. Reference lists and websites were also searched and key researchers were contacted. Studies were included if they reported the prevalence of any symptom or condition that included the word "pain" in Gulf War veterans and in a comparison group of non-Gulf veterans. 2401 abstracts were independently reviewed by two authors. RESULTS: Twenty studies fulfilled the inclusion criteria. Five main sites of pain were identified (muscle, joint, chest/heart, back and abdominal pain) and separate meta-analyses were performed to summarise the results related to each site. A greater proportion of Gulf veterans reported symptoms at each site of pain when compared to a non-Gulf military group. Gulf deployment was most strongly associated with abdominal pain, with Gulf veterans being more than three times more likely to report such pain than a comparison group (OR 3.23; 95%CI 2.31–4.51). Statistical heterogeneity between study estimates was significant, probably due to variation in measured periods of prevalence and symptom measurement methods. CONCLUSION: A higher proportion of veterans of the Persian Gulf War of 1991 reported symptoms of pain than military comparison groups. This is consistent with previously demonstrated increased reporting of more general symptoms (fatigue, multiple chemical sensitivity, post traumatic stress disorder) in these veterans compared with non-Gulf military groups. However, the primary studies were heterogeneous and varied greatly in quality

Outcome of a risk-related therapeutic strategy used prospectively in a population-based study of Hodgkin's lymphoma in adolescents

The aim was to assess outcome in a population-based cohort of adolescents with Hodgkin's lymphoma (HL) diagnosed in the UK's northern region over a 10-year period. Among a population of 3.09 million, 55 of 676 patients (8%) diagnosed with HL were aged 13–19. Seven had nodular lymphocyte-predominant HL, 48 classical HL (cHL). Of the latter, 36 were ⩾16 years. Application of the Scottish and Newcastle Lymphoma Group (SNLG) prognostic index meant 21 patients were considered high risk (index ⩾0.5). They received PVACEBOP multi-agent chemotherapy as primary therapy. Standard risk patients (SNLG index <0.5) were treated with standard ChlVPP or ABVD chemotherapy±radiotherapy. Scottish and Newcastle Lymphoma Group indexing is not valid for patients under 16. Twelve patients therefore received UKCCSG protocols (n=8), ABVD plus radiotherapy (n=2), or PVACEBOP (n=2). Forty-six patients with cHL (96%) achieved complete remission. Seven patients relapsed but all entered complete remission after salvage therapy. Five patients died: three of HL, one in an accident and one of disseminated varicella complicating cystic fibrosis. Five- and 10-year overall survival was 93 and 86%, respectively; disease-specific survival was 95 and 92%. The data suggest that older adolescents with high-risk HL require intensive protocols as primary therapy to secure optimal outcome

Burden, coping, physical symptoms and psychological morbidity in caregivers of functionally dependent family members

Objectives: this study assessed burden, coping, physical symptoms and psychological morbidity in caregivers of functionally dependent family members. Methods: fifty family caregivers completed self-reported measures of burden, physical symptoms, psychological morbidity and coping strategies. Results: there was a significant negative correlation between coping strategies and the different clinical variables, as well as a significant positive correlation between coping strategies and duration of care. It appears that the stronger bond between caregiver and family member leads to a poorer use of adaptive coping strategies. It also appears that the deterioration of the relationship between them and the lower perceived self-efficacy are more prominente in caregivers of family members with cognitive impairment, indicating that caregivers with family members without cognitive impairment face fewer difficulties. Conclusion: these results emphasize the need for interventions to include coping strategies, since they are important in reducing caregivers’ burden, psychological morbidity and physical symptoms

Changes in timber haul emissions in the context of shifting forest management and infrastructure

<p>Abstract</p> <p>Background</p> <p>Although significant amounts of carbon may be stored in harvested wood products, the extraction of that carbon from the forest generally entails combustion of fossil fuels. The transport of timber from the forest to primary milling facilities may in particular create emissions that reduce the net sequestration value of product carbon storage. However, attempts to quantify the effects of transport on the net effects of forest management typically use relatively sparse survey data to determine transportation emission factors. We developed an approach for systematically determining transport emissions using: 1) -remotely sensed maps to estimate the spatial distribution of harvests, and 2) - industry data to determine landscape-level harvest volumes as well as the location and processing totals of individual mills. These data support spatial network analysis that can produce estimates of fossil carbon released in timber transport.</p> <p>Results</p> <p>Transport-related emissions, evaluated as a fraction of transported wood carbon at 4 points in time on a landscape in western Montana (USA), rose from 0.5% in 1988 to 1.7% in 2004 as local mills closed and spatial patterns of harvest shifted due to decreased logging on federal lands.</p> <p>Conclusion</p> <p>The apparent sensitivity of transport emissions to harvest and infrastructure patterns suggests that timber haul is a dynamic component of forest carbon management that bears further study both across regions and over time. The monitoring approach used here, which draws only from widely available monitoring data, could readily be adapted to provide current and historical estimates of transport emissions in a consistent way across large areas.</p

Percutaneous coronary intervention of native coronary artery versus saphenous vein graft in patients with prior coronary artery bypass graft surgery: Rationale and design of the multicenter, randomized PROCTOR trial.

BACKGROUND: Patients with prior coronary artery bypass grafting (CABG) frequently require repeat percutaneous revascularization due to advanced age, progressive coronary artery disease and bypass graft failure. Percutaneous coronary intervention (PCI) of either the bypass graft or the native coronary artery may be performed. Randomized trials comparing native vessel PCI with bypass graft PCI are lacking and long-term outcomes have not been reported. METHODS: PROCTOR (NCT03805048) is a prospective, multicenter, randomized controlled trial, that will include 584 patients presenting with saphenous vein graft (SVG) failure and a clinical indication for revascularization, as determined by the local Heart Team. The trial is designed to compare the clinical and angiographic outcomes in patients randomly allocated in a 1:1 fashion to either a strategy of native vessel PCI or SVG PCI. The primary study endpoint is a 3-year composite of major adverse cardiac events (MACE: all-cause mortality, non-fatal target coronary territory myocardial infarction [MI], or clinically driven target coronary territory revascularization). At 3-years, after evaluation of the primary endpoint, follow-up invasive coronary angiography will be performed. Secondary endpoints comprise individual components of MACE at 1, 3 and 5 years follow-up, PCI-related MI, MI >48 hours after index PCI, target vessel failure, target lesion revascularization, renal failure requiring renal-replacement therapy, angiographic outcomes at 3-years and quality of life (delta Seattle Angina Questionnaire, Canadian Cardiovascular Society Grading Scale and Rose Dyspnea Scale). CONCLUSION: PROCTOR is the first randomized trial comparing an invasive strategy of native coronary artery PCI with SVG PCI in post-CABG patients presenting with SVG failure

Age differences in physiological responses to self-paced and incremental V˙O2max\dot V O_{2max} testing

Purpose: A self-paced maximal exercise protocol has demonstrated higher $\dot V O_{2max}$ values when compared against traditional tests. The aim was to compare physiological responses to this self-paced $\dot V O_{2max}$ protocol (SPV) in comparison to a traditional ramp $\dot V O_{2max}$ (RAMP) protocol in young (18–30 years) and old (50–75 years) participants. Methods: Forty-four participants (22 young; 22 old) completed both protocols in a randomised, counter-balanced, crossover design. The SPV included 5 × 2 min stages, participants were able to self-regulate their power output (PO) by using incremental ‘clamps’ in ratings of perceived exertion. The RAMP consisted of either 15 or 20 W min$^{−1}$. Results: Expired gases, cardiac output (Q), stroke volume (SV), muscular deoxyhaemoglobin (deoxyHb) and electromyography (EMG) at the vastus lateralis were recorded throughout. Results demonstrated significantly higher $\dot V O_{2max}$ in the SPV (49.68 ± 10.26 ml kg$^{−1}$ min$^{−1}$) vs. the RAMP (47.70 ± 9.98 ml kg$^{−1}$ min$^{−1}$) in the young, but not in the old group (>0.05). Q and SV were significantly higher in the SPV vs. the RAMP in the young (0.05). No differences seen in deoxyHb and EMG for either age groups (>0.05). Peak PO was significantly higher in the SPV vs. the RAMP in both age groups (<0.05). Conclusion: Findings demonstrate that the SPV produces higher $\dot V O_{2max}$, peak Q and SV values in the young group. However, older participants achieved similar $\dot V O_{2max}$ values in both protocols, mostly likely due to age-related differences in cardiovascular responses to incremental exercise, despite them achieving a higher physiological workload in the SPV

Changes in physical health among participants in a multidisciplinary health programme for long-term unemployed persons

Background. The relationship between poor health and unemployment is well established. Health promotion among unemployed persons may improve their health. The aims of this study were to investigate characteristics of non-participants and drop-outs in a multidisciplinary health promotion programme for long-term unemployed persons with health complaints, to evaluate changes in physical health among participants, and to investigate determinants of improvement in physical health. Methods. A longitudinal, non-controlled design was used. The programme consisted of two weekly exercise sessions and one weekly cognitive session during 12 weeks. The main outcome measures were body mass index, blood pressure, cardiorespiratory fitness, abd

The Predicted Secretome of the Plant Pathogenic Fungus Fusarium graminearum: A Refined Comparative Analysis

The fungus Fusarium graminearum forms an intimate association with the host species wheat whilst infecting the floral tissues at anthesis. During the prolonged latent period of infection, extracellular communication between live pathogen and host cells must occur, implying a role for secreted fungal proteins. The wheat cells in contact with fungal hyphae subsequently die and intracellular hyphal colonisation results in the development of visible disease symptoms. Since the original genome annotation analysis was done in 2007, which predicted the secretome using TargetP, the F. graminearum gene call has changed considerably through the combined efforts of the BROAD and MIPS institutes. As a result of the modifications to the genome and the recent findings that suggested a role for secreted proteins in virulence, the F. graminearum secretome was revisited. In the current study, a refined F. graminearum secretome was predicted by combining several bioinformatic approaches. This strategy increased the probability of identifying truly secreted proteins. A secretome of 574 proteins was predicted of which 99% was supported by transcriptional evidence. The function of the annotated and unannotated secreted proteins was explored. The potential role(s) of the annotated proteins including, putative enzymes, phytotoxins and antifungals are discussed. Characterisation of the unannotated proteins included the analysis of Pfam domains and features associated with known fungal effectors, for example, small size, cysteine-rich and containing internal amino acid repeats. A comprehensive comparative genomic analysis involving 57 fungal and oomycete genomes revealed that only a small number of the predicted F. graminearum secreted proteins can be considered to be either species or sequenced strain specific

Wnt and Hedgehog Are Critical Mediators of Cigarette Smoke-Induced Lung Cancer

BACKGROUND: Lung cancer is the leading cause of cancer death in the world, and greater than 90% of lung cancers are cigarette smoke-related. Current treatment options are inadequate, because the molecular basis of cigarette-induced lung cancer is poorly understood. METHODOLOGY/PRINCIPAL FINDINGS: Here, we show that human primary or immortalized bronchial epithelial cells exposed to cigarette smoke for eight days in culture rapidly proliferate, show anchorage-independent growth, and form tumors in nude mice. Using this model of the early stages of smoke-induced tumorigenesis, we examined the molecular changes leading to lung cancer. We observed that the embryonic signaling pathways mediated by Hedgehog and Wnt are activated by smoke. Pharmacological inhibition of these pathways blocked the transformed phenotype. CONCLUSIONS/SIGNIFICANCE: These experiments provide a model in which the early stages of smoke-induced tumorigenesis can be elicited, and should permit us to identify molecular changes driving this process. Results obtained so far indicate that smoke-induced lung tumors are driven by activation of two embryonic regulatory pathways, Hedgehog (Hh) and Wnt. Based on the current and emerging availability of drugs to inhibit Hh and Wnt signaling, it is possible that an understanding of the role of Hh and Wnt in lung cancer pathogenesis will lead to the development of new therapies