Lääketutka - Löytöretkeilyä ihmisten keskusteluihin omasta terveydestään

Peer reviewe

CD24 Expression and differential resistance to chemotherapy in triple-negative breast cancer.

Breast cancer (BC) is a leading cause of cancer-related death in women. Adjuvant systemic chemotherapies are effective in reducing risks of recurrence and have contributed to reduced BC mortality. Although targeted adjuvant treatments determined by biomarkers for endocrine and HER2-directed therapies are largely successful, predicting clinical benefit from chemotherapy is more challenging. Drug resistance is a major reason for treatment failures. Efforts are ongoing to find biomarkers to select patients most likely to benefit from chemotherapy. Importantly, cell surface biomarkers CD44+/CD24- are linked to drug resistance in some reports, yet underlying mechanisms are largely unknown. This study focused on the potential role of CD24 expression in resistance to either docetaxel or doxorubicin in part by the use of triple-negative BC (TNBC) tissue microarrays. In vitro assays were also done to assess changes in CD24 expression and differential drug susceptibility after chemotherapy. Further, mouse tumor xenograft studies were done to confirm in vitro findings. Overall, the results show that patients with CD24-positive TNBC had significantly worse overall survival and disease-free survival after taxane-based treatment. Also, in vitro cell studies show that CD44+/CD24+/high cells are more resistant to docetaxel, while CD44+/CD24-/low cells are resistant to doxorubicin. Both in vitro and in vivo studies show that cells with CD24-knockdown are more sensitive to docetaxel, while CD24-overexpressing cells are more sensitive to doxorubicin. Further, mechanistic studies indicate that Bcl-2 and TGF-βR1 signaling via ATM-NDRG2 pathways regulate CD24. Hence, CD24 may be a biomarker to select chemotherapeutics and a target to overcome TNBC drug resistance

Micromechanical analysis of kinematic hardening in natural clay

This paper presents a micromechanical analysis of the macroscopic behaviour of natural clay. A microstructural stress-strain model for clayey material has been developed which considers clay as a collection of clusters. The deformation of a representative volume of the material is generated by mobilizing and compressing all the clusters along their contact planes. Numerical simulations of multistage drained triaxial stress paths on Otaniemi clay have been performed and compared the numerical results to the experimental ones in order to validate the modelling approach. Then, the numerical results obtained at the microscopic level were analysed in order to explain the induced anisotropy observed in the clay behaviour at the macroscopic level. The evolution of the state variables at each contact plane during loading can explain the changes in shape and position in the stress space of the yield surface at the macroscopic level, as well as the rotation of the axes of anisotropy of the material

Livestock overgrazing disrupts the positive associations between soil biodiversity and nitrogen availability

8 páginas.- 4 figuras.- 1 tabla.- 64 referencias.- Additional supporting information may be found online in the Supporting Information sectionLivestock overgrazing influences both microbial communities and nutrient cycling in terrestrial ecosystems. However, the role of overgrazing in regulating the relationship between soil biodiversity and nitrogen availability remains largely unexplored.We performed long-term grazing exclusion experiments across eight sites along precipitation gradient covering three major types of grassland in northern China to compare the linkage between soil microbial diversity and N availability in overgrazed versus non-grazed conditions.We found a significantly positive association between fungal diversity and soil available N in non-grazed grasslands. However, the positive association was absent in overgrazed environments. Bacterial diversity is not related to soil available N in either non-grazed or overgrazed grasslands. Moreover, in bacterial community, we found a positive link between the relative abundance of Actinobacteria with soil available N in non-grazed, but not overgrazed, grasslands. Instead we found the links between relative abundance of Bacteroidetes and Acidobacteria with soil available N in overgrazed grasslands, but not non-grazed, grasslands.Synthesis. Our work provides evidence that the relationships between microbial diversity and ecosystem functions are context-dependent, and so microbial community diversity is likely not the major driver of soil N mineralization in overgrazed grasslands. Our study suggests that high intensity anthropogenic activities in grasslands restrains the capacity of diverse soil microbial communities to sustain ecosystem function, and more broadly the capacity of entire ecosystems to maintain important ecosystem processes such as plant production. Our study also indicates that the fundamental microbial communities associated with N availability change with differing land management strategies (e.g. livestock grazing).National Natural Science Foundation of China, Grant/Award Number: 31772652, U1603235, 31660679 and 31770500; National Key Research and Development Program of China, Grant/Award Number: 2016YFC0500602; Program for Introducing Talents to Universities, Grant/Award Number: B16011; Ministry of Education Innovation Team Development Plan, Grant/Award Number: 2013-373; Innovative Team of Grassland Resources from the Ministry of Education of China, Grant/Award Number: IRT_17R59; Horizon 2020 Framework Program, Grant/Award Number: H2020-MSCA-IF-2016Peer reviewe

Genetic Variants in Inflammation-Related Genes Are Associated with Radiation-Induced Toxicity Following Treatment for Non-Small Cell Lung Cancer

Treatment of non-small cell lung cancer (NSCLC) with radiotherapy or chemoradiotherapy is often accompanied by the development of esophagitis and pneumonitis. Identifying patients who might be at increased risk for normal tissue toxicity would help in determination of the optimal radiation dose to avoid these events. We profiled 59 single nucleotide polymorphisms (SNPs) from 37 inflammation-related genes in 173 NSCLC patients with stage IIIA/IIIB (dry) disease who were treated with definitive radiation or chemoradiation. For esophagitis risk, nine SNPs were associated with a 1.5- to 4-fold increase in risk, including three PTGS2 (COX2) variants: rs20417 (HR:1.93, 95% CI:1.10–3.39), rs5275 (HR:1.58, 95% CI:1.09–2.27), and rs689470 (HR:3.38, 95% CI:1.09–10.49). Significantly increased risk of pneumonitis was observed for patients with genetic variation in the proinflammatory genes IL1A, IL8, TNF, TNFRSF1B, and MIF. In contrast, NOS3:rs1799983 displayed a protective effect with a 45% reduction in pneumonitis risk (HR:0.55, 95% CI:0.31–0.96). Pneumonitis risk was also modulated by polymorphisms in anti-inflammatory genes, including genetic variation in IL13. rs20541 and rs180925 each resulted in increased risk (HR:2.95, 95% CI:1.14–7.63 and HR:3.23, 95% CI:1.03–10.18, respectively). The cumulative effect of these SNPs on risk was dose-dependent, as evidenced by a significantly increased risk of either toxicity with an increasing number of risk genotypes (P<0.001). These results suggest that genetic variations among inflammation pathway genes may modulate the development of radiation-induced toxicity and, ultimately, help in identifying patients who are at an increased likelihood for such events

Trousseau's Syndrome in Association with Cholangiocarcinoma: Positive Tests for Coagulation Factors and Anticardiolipin Antibody

Thromboembolic events are reported to occur with a high frequency in the setting of malignancy. However, reports on an association between cholangiocarcinoma and pulmonary thromboembolism, thus far, are almost lacking. We present here an unusual case of a 56-yr-old patient presenting cholangiocarcinoma and unexplained pulmonary thromboembolism. The patient had been quite healthy before the diagnosis. Coagulation tests showed elevated levels of fibrinogen, fibrinogen degradation product (FDP), D-dimer, and IgM anticardiolipin antibody (aCL Ab). The thromboemboli were resolved 3 weeks after anticoagulant therapy using low-molecular-weight-heparin. Then, follow-up coagulation tests showed a marked decrease to normal in aCL Ab titer as well as the normalization of FDP and D-dimer levels. In this case, we describe pulmonary thromboembolism caused by hypercoagulable state associated with cholangiocarcinoma and speculate that such a thrombotic phenomenon could be regressed by anticoagulant therapy

Screening of Brain Metastasis with Limited Magnetic Resonance Imaging (MRI): Clinical Implications of Using Limited Brain MRI During Initial Staging for Non-small Cell Lung Cancer Patients

The purpose of this prospective study was to determine whether using magnetic resonance imaging (MRI) for early screening for brain metastases (BM) can improve quality of life, survival in patients with non-small cell lung cancer (NSCLC). The study group comprised 183 patients newly diagnosed with NSCLC. All patients underwent limited brain MRI and routine workups. The control group comprised 131 patients with NSCLC who underwent limited brain MRI only if they had neurologic symptoms. The incidence of BM was 20.8% (38/183) in the study group and 4.6% (6/131) in the control group. The rate of upstaging based on the MRI data was 13.5% (15/111) overall and 15.9% (11/69) in patients that had been considered initially to be resectable surgically. There was no significant difference in survival outcome between the groups. Patients who had BM alone had a greater overall survival time (49 weeks) than those who had multiple systemic metastases (27 weeks; p=0.0307). In conclusions, limited brain MRI appears to be a useful, cost-effective method to screen for BM at the time of initial staging. And it may facilitate timely treatment of patients with NSCLC and improve their survival and quality of life

Male Germ Cell-Specific RNA Binding Protein RBMY: A New Oncogene Explaining Male Predominance in Liver Cancer

Male gender is a risk factor for the development of hepatocellular carcinoma (HCC) but the mechanisms are not fully understood. The RNA binding motif gene on the Y chromosome (RBMY), encoding a male germ cell-specific RNA splicing regulator during spermatogenesis, is aberrantly activated in human male liver cancers. This study investigated the in vitro oncogenic effect and the possible mechanism of RBMY in human hepatoma cell line HepG2 and its in vivo effect with regards to the livers of human and transgenic mice. RBMY expression in HepG2 cells was knocked down by RNA interference and the cancer cell phenotype was characterized by soft-agar colony formation and sensitivity to hydrogen-peroxide-induced apoptosis. The results revealed that RBMY knockdown reduced the transformation and anti-apoptotic efficiency of HepG2 cells. The expression of RBMY, androgen receptor (AR) and its inhibitory variant AR45, AR-targeted genes insulin-like growth factor 1 (IGF-1) and insulin-like growth factor binding protein 3 (IGFBP-3) was analyzed by quantitative RT-PCR. Up-regulation of AR45 variant and reduction of IGF-1 and IGFBP-3 expression was only detected in RBMY knockdown cells. Moreover, RBMY positive human male HCC expressed lower level of AR45 as compared to RBMY negative HCC tissues. The oncogenic properties of RBMY were further assessed in a transgenic mouse model. Liver-specific RBMY transgenic mice developed hepatic pre-cancerous lesions, adenoma, and HCC. RBMY also accelerated chemical carcinogen-induced hepatocarcinogenesis in transgenic mice. Collectively, these findings suggest that Y chromosome-specific RBMY is likely involved in the regulation of androgen receptor activity and contributes to male predominance of HCC

Small Molecule Amiloride Modulates Oncogenic RNA Alternative Splicing to Devitalize Human Cancer Cells

Alternative splicing involves differential exon selection of a gene transcript to generate mRNA and protein isoforms with structural and functional diversity. Abnormal alternative splicing has been shown to be associated with malignant phenotypes of cancer cells, such as chemo-resistance and invasive activity. Screening small molecules and drugs for modulating RNA splicing in human hepatocellular carcinoma cell line Huh-7, we discovered that amiloride, distinct from four pH-affecting amiloride analogues, could “normalize” the splicing of BCL-X, HIPK3 and RON/MISTR1 transcripts. Our proteomic analyses of amiloride-treated cells detected hypo-phosphorylation of splicing factor SF2/ASF, and decreased levels of SRp20 and two un-identified SR proteins. We further observed decreased phosphorylation of AKT, ERK1/2 and PP1, and increased phosphorylation of p38 and JNK, suggesting that amiloride treatment down-regulates kinases and up-regulates phosphatases in the signal pathways known to affect splicing factor protein phosphorylation. These amiloride effects of “normalized” oncogenic RNA splicing and splicing factor hypo-phosphorylation were both abrogated by pre-treatment with a PP1 inhibitor. Global exon array of amiloride-treated Huh-7 cells detected splicing pattern changes involving 584 exons in 551 gene transcripts, many of which encode proteins playing key roles in ion transport, cellular matrix formation, cytoskeleton remodeling, and genome maintenance. Cellular functional analyses revealed subsequent invasion and migration defects, cell cycle disruption, cytokinesis impairment, and lethal DNA degradation in amiloride-treated Huh-7 cells. Other human solid tumor and leukemic cells, but not a few normal cells, showed similar amiloride-altered RNA splicing with devitalized consequence. This study thus provides mechanistic underpinnings for exploiting small molecule modulation of RNA splicing for cancer therapeutics