We present a set of recommendations for the presentation of LHC results on searches for new physics, which are aimed at providing a more efficient flow of scientific information between the ...experimental collaborations and the rest of the high energy physics community, and at facilitating the interpretation of the results in a wide class of models. Implementing these recommendations would aid the full exploitation of the physics potential of the LHC.
Lung cancer stem cells (CSCs) have recently been isolated from lung cancer patient samples and have been reported to be responsible for tumor initiation, treatment resistance and tumor recurrence. We ...have previously shown that oncolytic Newcastle disease virus (NDV), strain FMW (NDV/FMW) induces apoptosis in drug-resistant lung cancer cells. However, how NDV exerts its oncolytic effect on lung CSCs remains to be investigated. Here we show that NDV/FMW replicates in, and lyses CSC-enriched lung cancer spheroids and inhibits the 3D growth potential of lung cancer spheroid and agar colonies. We demonstrate that NDV/FMW triggers caspase-dependent apoptosis in lung cancer spheroids as shown by increased caspase-3 processing and Poly (ADP-ribose) polymerase (PARP) cleavage. Notably, NDV/FMW infection results in the degradation of microtubule-associated protein 1 light chain 3 (LC3) II and P62, two hallmarks of autophagy maturation, indicating that NDV/FMW promotes autophagy flux in lung cancer cell spheroids. This was further confirmed by the appearance of an increased number of double-membrane vesicles as detected by transmission electron microscopy. We also show that NDV/FMW promotes autophagy degradation in lung cancer spheroids via inhibition of the AKT/mTOR pathway. In addition, treatment of spheroids with the autophagy inhibitor, chloroquine increases NDV/FMW-induced cytotoxicity. Collectively, our data show that oncolytic NDV/FMW may be a potential strategy in targeting lung CSCs.
Non-small cell lung cancer (NSCLC) is the most common cause of cancer related death in the world. Cisplatin and carboplatin are the most commonly used cytotoxic chemotherapeutic agents to treat the ...disease. These agents, usually combined with drugs such as gemcitabine or pemetrexed, induce objective tumor responses in only 20-30% of patients. Aberrant epigenetic regulation of gene expression is a frequent event in NSCLC. In this article we review the emerging evidence that epigenetics and the cellular machinery involved with this type of regulation may be key elements in the development of cisplatin resistance in NSCLC.
To evaluate the potential therapeutic utility of histone deacetylase inhibitors (HDACi) in targeting VEGF receptors in non-small-cell lung cancer.
Non-small-cell lung cancer cells were screened for ...the VEGF receptors at the mRNA and protein levels, while cellular responses to various HDACi were examined.
Significant effects on the regulation of the VEGF receptors were observed in response to HDACi. These were associated with decreased secretion of VEGF, decreased cellular proliferation and increased apoptosis which could not be rescued by addition of exogenous recombinant VEGF. Direct remodeling of the VEGFR1 and VEGFR2 promoters was observed. In contrast, HDACi treatments resulted in significant downregulation of the Neuropilin receptors.
Epigenetic targeting of the Neuropilin receptors may offer an effective treatment for lung cancer patients in the clinical setting.
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Background: Mismatch repair (MMR) deficiency and microsatellite instability (MSI) are predictive biomarkers for immunotherapy response. The best approach to identify patients with such tumors is ...unclear in prostate cancer. Methods: This study included men diagnosed with primary prostate cancer during prospective follow-up of the Health Professionals Follow-up Study (HPFS) and Physicians’ Health Study (PHS). The highest-grade/index lesions of tumor tissue from radical prostatectomy (95%) or transurethral resections of the prostate were mounted in triplicate on tissue microarrays. Immunohistochemistry for the MMR proteins MLH1, MSH2, MSH6, and PMS2 was performed, with scoring as MMR-deficient requiring a visible staining in a non-tumor internal positive control of the same case. For validation, a polymerase chain reaction-based MSI assay (Idylla MSI Test, Biocartis) was performed on tumor DNA of MMR-deficient cases and a selection of MMR-intact cases. Results: The study included 1016 men with prostate cancer. Tumor stage was predominantly pathologically localized (71% stage pT1/2, 18% T3a/b) with a full distribution of Gleason scores, including 20% Gleason score 6 (grade group 1), 36% 3+4 (grade group 2), 23% 4+3 (grade group 3), 8% 8 (grade group 4) and 13% 9-10 (grade group 5). MMR tumor scoring could be performed for MLH1 in 747 cases (75% of those with tumor tissue), for MSH2 in 903 cases (90%), for MSH6 in 708 cases (74%), and for PMS2 in 703 cases (72%). The remaining tumors were unevaluable due to lack of non-tumor tissue necessary as an internal positive control. Of the 903 tumors evaluable for MSH2 protein loss, 4 tumors had loss of MSH2 (prevalence 0.4%, 95% confidence interval CI 0.2–1.1%), and 3 of 708 evaluable tumors had concomitant loss of MSH6 (prevalence 0.4%, 95% CI 0.1–1.2%). No tumor had loss of MLH1 or PMS2. The MMR-deficient tumors had Gleason scores of 3+4, 8 (two cases), and 9–10. Tumor DNA of 1 of the 4 MMR-deficient tumors met the manufacturer’s cut-off for MSI-high; two additional MMR-deficient cases had non-zero repeats, with good reproducibility between tumor cores and technical replicates. One MSH2-deficient tumor and 6 DNA samples from 3 MMR-intact cases had repeat scores of zero. Conclusions: In this nationwide prospective study, MMR deficiency was rare in primary, surgically treated prostate cancer. This low prevalence contrasts with hospital-based studies of MMR deficiency and MSI that may have represented tumors with certain clinical features. The low prevalence and the need for an internal positive control for reliable scoring calls into question to what extent immunohistochemistry-based screening for MMR deficiency on limited tissue specimens, such as prostate biopsies, is routinely feasible.
Recent research has established Schmidt Hammer exposure dating (SHED) as an effective method for dating glacial landforms in the UK. This paper presents new data and discussion to clarify and to ...evaluate calibration procedures. These make a distinction between Schmidt Hammer drift following use (instrument calibration), and variation between both individual Schmidt Hammers and between user strategies when utilising age-calibration curves (age calibration). We show that while test anvil methods are useful for verifying that Schmidt Hammers maintain their standard R-values, they are inappropriate for instrument calibration except for the hardest natural rock surfaces (R-values: ≥ 70). A range of surfaces were tested using 3 N-Type Schmidt Hammers, which showed that existing anvil calibration procedures led to consistent overestimation of R-values by up to 17.9%. In contrast, new calibration procedures, which are based on the use of a calibration point which lies within the range of R-values measured in the field Dortch et al. 2016, Quat. Geochron., 35, 67–68, limit variance to maximum of 4.4% for surfaces typically tested by Quaternary researchers (R-values: 25–60). Moreover, these new calibration procedures are more appropriate for age calibration as they incorporate operator variance through choice of sampling location. New calibration procedures are used to compile an updated age-calibration curve based upon 54 granite surfaces (R2 = 0.94, p < .01) from across Scotland, NW England and Ireland. The inclusion of a further 29 terrestrial cosmogenic nuclide (TCN) exposure ages extends the calibration period to 0.8–23.8 ka, covering the entire post-Last Glacial Maximum (LGM) history of the British-Irish Ice Sheet. To facilitate comparison between studies, an online calculator is made available at http://shed.earth for Schmidt Hammer instrument and age calibration and SHED exposure age calculation. The SHED-Earth calculator provides a rapid and accessible means of exposure age calculation to encourage wider and more consistent application of SHED throughout the British Isles.
Pleural mesothelioma (PM) is an aggressive malignancy with increasing prevalence and poor prognosis. Real-life data are a unique approach to reflect the reality of PM epidemiology, treatment, and ...prognosis in Europe.
A joint analysis of the European Thoracic Oncology Platform Mesoscape and the European Society of Thoracic Surgeons (ESTS) databases was performed to better understand the characteristics and epidemiology of PM, including histologic subtype, staging, and treatment. Overall survival (OS) was assessed, adjusting for parameters of clinical interest.
The analysis included 2766 patients (Mesoscape: 497/10 centers/ESTS: 2269/77 centers). The primary histologic subtype was epithelioid (71%), with 57% patients on stages III to IV. Within Mesoscape, the patients received either multimodality (59%) or palliative intention treatment (41%). The median follow-up was 47.2 months, on the basis of 1103 patients (Mesoscape: 491/ESTS: 612), with 823 deaths, and median OS was 17.4 months. In multivariable analysis, female sex, epithelioid subtype, and lower stage were associated with longer OS, when stratifying by cohort, age, and Eastern Cooperative Oncology Group Performance Status. Within Mesoscape, multimodality treatment including surgery was predictive of longer OS (hazard ratio = 0.56, 95% confidence interval: 0.45–0.69), adjusting for sex, histologic subtype, and Eastern Cooperative Oncology Group Performance Status. Overall, surgical candidates with a macroscopic complete resection had a significantly longer median OS compared with patients with R2 (25.2 m versus 16.4 m; log-rank p < 0.001).
This combined European Thoracic Oncology Platform/ESTS database analysis offers one of the largest databases with detailed clinical and pathologic outcome. Our finding reflects a benefit for selected patients that undergo multimodality treatment, including macroscopic complete resection, and represents a valuable resource to inform the epidemiology and treatment options for individual patients.
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