IRAK4 mediates colitis-induced tumorigenesis and chemoresistance in colorectal cancer

Aberrant activation of the NF-κB transcription factors underlies chemoresistance in various cancer types, including colorectal cancer (CRC). Targeting the activating mechanisms, particularly with inhibitors to the upstream IκB kinase (IKK) complex, is a promising strategy to augment the effect of chemotherapy. However, clinical success has been limited, largely because of low specificity and toxicities of tested compounds. In solid cancers, the IKKs are driven predominantly by the Toll-like receptor (TLR)/IL-1 receptor family members, which signal through the IL-1 receptor-associated kinases (IRAKs), with isoform 4 (IRAK4) being the most critical. The pathogenic role and therapeutic value of IRAK4 in CRC have not been investigated. We found that IRAK4 inhibition significantly abrogates colitis-induced neoplasm in APCMin/+ mice, and bone marrow transplant experiments showed an essential role of IRAK4 in immune cells during neoplastic progression. Chemotherapy significantly enhances IRAK4 and NF-κB activity in CRC cells through upregulating TLR9 expression, which can in turn be suppressed by IRAK4 and IKK inhibitors, suggesting a feed-forward pathway that protects CRC cells from chemotherapy. Lastly, increased tumor phospho-IRAK4 staining or IRAK4 mRNA expression is associated with significantly worse survival in CRC patients. Our results support targeting IRAK4 to improve the effects of chemotherapy and outcomes in CRC

Medical graduates’ preparedness to practice: A comparison of undergraduate medical school training

Background: There is evidence that newly qualified doctors do not feel prepared to start work. This study examined views of first year Foundation doctors (F1s) regarding how prepared they felt by their undergraduate medical education for skills required during the first Foundation training year in relation to their type of training. Method: One-hundred and eighty two F1s completed a questionnaire during their first rotation of Foundation training. Analysis was conducted by type of medical school training: Problem-Based Learning (PBL), Traditional or Reformed. Results: F1s from medical schools with a PBL curriculum felt better prepared for tasks associated with communication and team working, and paperwork than graduates from the other medical school types; but the majority of F1s from all three groups felt well prepared for most areas of practice. Less than half of graduates in all three groups felt well prepared to deal with a patient with neurological/visual problems; write referral letters; understand drug interactions; manage pain; and cope with uncertainty. F1s also indicated that lack of induction or support on starting work was affecting their ability to work in some areas. Conclusions: Whilst F1s from medical schools with a PBL curriculum did feel better prepared in multiple areas compared to graduates from the other medical school types, specific areas of unpreparedness related to undergraduate and postgraduate medical training were identified across all F1s. These areas need attention to ensure F1s are optimally prepared for starting work

Kepler observations of variability in B-type stars

The analysis of the light curves of 48 B-type stars observed by Kepler is presented. Among these are 15 pulsating stars, all of which show low frequencies characteristic of SPB stars. Seven of these stars also show a few weak, isolated high frequencies and they could be considered as SPB/beta Cep hybrids. In all cases the frequency spectra are quite different from what is seen from ground-based observations. We suggest that this is because most of the low frequencies are modes of high degree which are predicted to be unstable in models of mid-B stars. We find that there are non-pulsating stars within the beta Cep and SPB instability strips. Apart from the pulsating stars, we can identify stars with frequency groupings similar to what is seen in Be stars but which are not Be stars. The origin of the groupings is not clear, but may be related to rotation. We find periodic variations in other stars which we attribute to proximity effects in binary systems or possibly rotational modulation. We find no evidence for pulsating stars between the cool edge of the SPB and the hot edge of the delta Sct instability strips. None of the stars show the broad features which can be attributed to stochastically-excited modes as recently proposed. Among our sample of B stars are two chemically peculiar stars, one of which is a HgMn star showing rotational modulation in the light curve.Comment: 19 pages, 11 figures, 4 table

Shear Strength Parameters of Improved Peat by Chemical Stabilizer.

The present research aimed to discuss the applicability of cationic grouts in geotechnical engineering. The effects of several cationic stabilizers such as monovalent (sodium silicate), divalent (calcium oxide and calcium chloride), and trivalent (aluminum hydroxide) were investigated on shear strength improvement of tropical peat samples. The unconfined compressive strength (UCS) tests were performed after the time frame of 7, 21, and 30 days as curing time, respectively. Apart from the physicochemical characteristics of the stabilized peat, scanning electron microscopy and energy-dispersive X-ray spectroscopy tests were also carried out to study the ongoing microstructural changes. It is to be noted that the shear strength values for peat samples rose to 8, 6, 6, and 4 % of sodium silicate, calcium oxide, calcium chloride, and aluminum hydroxide, respectively. The highest observed UCS outcome is the one taken from the calcium oxide where the UCS of treated peat after 30-day curing time increased to 76 kPa. The strength changes resulted from the various cationic stabilizers can best be explained via the consideration within the mineralogical composition as well as those physicochemical changes happening in the peat

Stromal and therapy-induced macrophage proliferation promotes PDAC progression and susceptibility to innate immunotherapy

Tumor-associated macrophages (TAMs) are abundant in pancreatic ductal adenocarcinomas (PDACs). While TAMs are known to proliferate in cancer tissues, the impact of this on macrophage phenotype and disease progression is poorly understood. We showed that in PDAC, proliferation of TAMs could be driven by colony stimulating factor-1 (CSF1) produced by cancer-associated fibroblasts. CSF1 induced high levels of p21 in macrophages, which regulated both TAM proliferation and phenotype. TAMs in human and mouse PDACs with high levels of p21 had more inflammatory and immunosuppressive phenotypes. p21 expression in TAMs was induced by both stromal interaction and/or chemotherapy treatment. Finally, by modeling p21 expression levels in TAMs, we found that p21-driven macrophage immunosuppression in vivo drove tumor progression. Serendipitously, the same p21-driven pathways that drive tumor progression also drove response to CD40 agonist. These data suggest that stromal or therapy-induced regulation of cell cycle machinery can regulate both macrophage-mediated immune suppression and susceptibility to innate immunotherapy

Combined KRAS-MAPK pathway inhibitors and HER2-directed drug conjugate is efficacious in pancreatic cancer

Targeting the mitogen-activated protein kinase (MAPK) cascade in pancreatic ductal adenocarcinoma (PDAC) remains clinically unsuccessful. We aim to develop a MAPK inhibitor-based therapeutic combination with strong preclinical efficacy. Utilizing a reverse-phase protein array, we observe rapid phospho-activation of human epidermal growth factor receptor 2 (HER2) in PDAC cells upon pharmacological MAPK inhibition. Mechanistically, MAPK inhibitors lead to swift proteasomal degradation of dual-specificity phosphatase 6 (DUSP6). The carboxy terminus of HER2, containing a TEY motif also present in extracellular signal-regulated kinase 1/2 (ERK1/2), facilitates binding with DUSP6, enhancing its phosphatase activity to dephosphorylate HER2. In the presence of MAPK inhibitors, DUSP6 dissociates from the protective effect of the RING E3 ligase tripartite motif containing 21, resulting in its degradation. In PDAC patient-derived xenograft (PDX) models, combining ERK and HER inhibitors slows tumour growth and requires cytotoxic chemotherapy to achieve tumour regression. Alternatively, MAPK inhibitors with trastuzumab deruxtecan, an anti-HER2 antibody conjugated with cytotoxic chemotherapy, lead to sustained tumour regression in most tested PDXs without causing noticeable toxicity. Additionally, KRAS inhibitors also activate HER2, supporting testing the combination of KRAS inhibitors and trastuzumab deruxtecan in PDAC. This study identifies a rational and promising therapeutic combination for clinical testing in PDAC patients

Investigating the Antiproliferative Activity of High Affinity DNA Aptamer on Cancer Cells

10.1371/journal.pone.0050964PLoS ONE81

Photometric multi-site campaign on the open cluster NGC 884 I. Detection of the variable stars

CONTEXT: Recent progress in the seismic interpretation of field beta Cep stars has resulted in improvements of the physics in the stellar structure and evolution models of massive stars. Further asteroseismic constraints can be obtained from studying ensembles of stars in a young open cluster, which all have similar age, distance and chemical composition. AIMS: To improve our comprehension of the beta Cep stars, we studied the young open cluster NGC 884 to discover new B-type pulsators, besides the two known beta Cep stars, and other variable stars. METHODS: An extensive multi-site campaign was set up to gather accurate CCD photometry time series in four filters (U, B, V, I) of a field of NGC884. Fifteen different instruments collected almost 77500 CCD images in 1286 hours. The images were calibrated and reduced to transform the CCD frames into interpretable differential light curves. Various variability indicators and frequency analyses were applied to detect variable stars in the field. Absolute photometry was taken to deduce some general cluster and stellar properties. RESULTS: We achieved an accuracy for the brightest stars of 5.7 mmag in V, 6.9 mmag in B, 5.0 mmag in I and 5.3 mmag in U. The noise level in the amplitude spectra is 50 micromag in the V band. Our campaign confirms the previously known pulsators, and we report more than one hundred new multi- and mono-periodic B-, A- and F-type stars. Their interpretation in terms of classical instability domains is not straightforward, pointing to imperfections in theoretical instability computations. In addition, we have discovered six new eclipsing binaries and four candidates as well as other irregular variable stars in the observed field.Comment: Accepted for publication in Astronomy and Astrophysics, 21 pages, 14 figures, 4 tables. The full appendix is available at http://www.ster.kuleuven.be/~sophies/Appendix.pdf (74 MB, 169 pages, 343 figures, 1 table

Enteropathy-associated T cell lymphoma subtypes are characterized by loss of function of SETD2

Enteropathy-associated T cell lymphoma (EATL) is a lethal, and the most common, neoplastic complication of celiac disease. Here, we defined the genetic landscape of EATL through whole-exome sequencing of 69 EATL tumors. SETD2 was the most frequently silenced gene in EATL (32% of cases). The JAK-STAT pathway was the most frequently mutated pathway, with frequent mutations in STAT5B as well as JAK1 , JAK3 , STAT3 , and SOCS1 . We also identified mutations in KRAS , TP53 , and TERT . Type I EATL and type II EATL (monomorphic epitheliotropic intestinal T cell lymphoma) had highly overlapping genetic alterations indicating shared mechanisms underlying their pathogenesis. We modeled the effects of SETD2 loss in vivo by developing a T cell–specific knockout mouse. These mice manifested an expansion of γδ T cells, indicating novel roles for SETD2 in T cell development and lymphomagenesis. Our data render the most comprehensive genetic portrait yet of this uncommon but lethal disease and may inform future classification schemes