Purpose: This study was designed to elucidate the role of amplification at 8q24 in the pathophysiology of ovarian and breast cancer
because increased copy number at this locus is one of the most ...frequent genomic abnormalities in these cancers.
Experimental Design: To accomplish this, we assessed the association of amplification at 8q24 with outcome in ovarian cancers using fluorescence
in situ hybridization to tissue microarrays and measured responses of ovarian and breast cancer cell lines to specific small interfering
RNAs against the oncogene MYC and a putative noncoding RNA, PVT1 , both of which map to 8q24.
Results: Amplification of 8q24 was associated with significantly reduced survival duration. In addition, small interfering RNA–mediated
reduction in either PVT1 or MYC expression inhibited proliferation in breast and ovarian cancer cell lines in which they were both amplified and overexpressed
but not in lines in which they were not amplified/overexpressed. Inhibition of PVT1 expression also induced a strong apoptotic response in cell lines in which it was overexpressed but not in lines in which
it was not amplified/overexpressed. Inhibition of MYC , on the other hand, did not induce an apoptotic response in cell lines in which MYC was amplified and overexpressed.
Conclusions: These results suggest that MYC and PVT1 contribute independently to ovarian and breast pathogenesis when overexpressed because of genomic abnormalities. They also
suggest that PVT1 -mediated inhibition of apoptosis may explain why amplification of 8q24 is associated with reduced survival duration in patients
treated with agents that act through apoptotic mechanisms.
Although many acute myeloid leukemia (AML) colony-forming cells (CFCs) and long-term culture–initiating cells (LTC-ICs) directly isolated from patients are actively cycling, quiescent progenitors are ...present in most samples. In the current study,3H-thymidine (3H-Tdr) suicide assays demonstrated that most NOD/SCID mouse leukemia-initiating cells (NOD/SL-ICs) are quiescent in 6 of 7 AML samples. AML cells in G0, G1, and S/G2+M were isolated from 4 of these samples using Hoechst 33342/pyroninY staining and cell sorting. The progenitor content of each subpopulation was consistent with the3H-Tdr suicide results, with NOD/SL-ICs found almost exclusively among G0cells while the cycling status of AML CFCs and LTC-ICs was more heterogeneous. Interestingly, after 72 hours in serum-free culture with or without Steel factor (SF), Flt-3 ligand (FL), and interleukin-3 (IL-3), most G0AML cells entered active cell cycle (percentage of AML cells remaining in G0at 72 hours, 1.2% to 37%, and 0% to 7.6% in cultures without and with growth factors GFs, respectively) while G0cells from normal lineage-depleted bone marrow remained quiescent in the absence of GF. All 4 AML samples showed evidence of autocrine production of 2 or more of SF, FL, IL-3, and granulocyte-macrophage colony-stimulating factor (GM-CSF). In addition, 3 of 4 samples contained an internal tandem duplication of theFLT3gene. In summary, quiescent leukemic cells, including NOD/SL-ICs, are present in most AML patients. Their spontaneous entry into active cell cycle in short-term culture might be explained by the deregulated GF signaling present in many AMLs.
Tailoring cancer treatment to tumor molecular characteristics promises to make personalized medicine a reality. However, reliable genetic profiling of archived clinical specimens has been hindered by ...limited sensitivity and high false-positive rates. Here, we describe a novel methodology, MMP-seq, which enables sensitive and specific high-throughput, high-content genetic profiling in archived clinical samples.
We first validated the technical performance of MMP-seq in 66 cancer cell lines and a Latin square cross-dilution of known somatic mutations. We next characterized the performance of MMP-seq in 17 formalin-fixed paraffin-embedded (FFPE) clinical samples using matched fresh-frozen tissue from the same tumors as benchmarks. To demonstrate the potential clinical utility of our methodology, we profiled FFPE tumor samples from 73 patients with endometrial cancer.
We demonstrated that MMP-seq enabled rapid and simultaneous profiling of a panel of 88 cancer genes in 48 samples, and detected variants at frequencies as low as 0.4%. We identified DNA degradation and deamination as the main error sources and developed practical and robust strategies for mitigating these issues, and dramatically reduced the false-positive rate. Applying MMP-seq to a cohort of endometrial tumor samples identified extensive, potentially actionable alterations in the PI3K (phosphoinositide 3-kinase) and RAS pathways, including novel PIK3R1 hotspot mutations that may disrupt negative regulation of PIK3CA.
MMP-seq provides a robust solution for comprehensive, reliable, and high-throughput genetic profiling of clinical tumor samples, paving the way for the incorporation of genomic-based testing into clinical investigation and practice.
Background: Lotensin has been shown to have a protective function in the early stage of chronic renal failure. However, its role in the intermediate and late stages of chronic renal failure remains ...largely unknown. The present study aimed to investigate the role and underlying mechanism of lotensin in advanced chronic kidney disease.
Methods: Female Wistar rats were randomly divided into three groups (n = 10): sham group, 5/6 nephrectomy (5/6 Nx) group, and lotensin group (oral administration of lotensin for 9 weeks following 5/6 Nx). Rats were sacrificed and pathological parameters were measured. Western blot assay and immunohistochemical staining were performed to detect the expression of transforming growth factor-β1 (TGF-β1) and α-smooth muscle actin (α-SMA) in kidney tissues.
Results: Compared to the 5/6 Nx group, lotensin administration significantly decreased 5/6 Nx-induced elevation in blood urea nitrogen, serum creatinine and 24-h urinary protein excretion (UPE) rates, but markedly increased red blood cell count, plasma albumin and hemoglobin levels, along with improved renal morphology. Mechanistically, lotensin dramatically downregulated the renal expression of TGF-β1 and α-SMA induced by 5/6 Nx.
Conclusions: Lotensin protects against advanced chronic kidney disease in rats with 5/6 Nx through the downregulation of TGF-β1 and α-SMA.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Investigating the effect of geocells on the erosion and deposition distribution of ephemeral gullies in the black soil area of Northeast China can provide a scientific basis for the allocation of ...soil and water conservation measures in ephemeral gullies. In this study, an artificial simulated confluence test and stereoscopic photogrammetry were used to analyze the distribution characteristics of erosion and deposition in ephemeral gullies protected by geocells and the effect of different confluence flows on the erosion process of ephemeral gullies. Results showed that when the confluence flow was larger, the effect of geocell was more evident, and the protection against ephemeral gully erosion was stronger. When the confluence flow rates were 0.6, 1.8, 2.4, and 3.0 m
3
/h, ephemeral gully erosion decreased by 37.84%, 26.09%, 21.40%, and 35.45%. When the confluence flow rates were 2.4 and 3.0 m
3
/h, the average sediment yield rate of the ephemeral gully was close to 2.14 kg/(m
2
·mm), and the protective effect of ephemeral gully erosion was enhanced. When the flow rate was higher, the surface fracture of the ephemeral gully was more serious. With an increase in confluence flow rate, the ratio of erosion to deposition increased gradually, the erosion area of ephemeral gullies was expanded, and erosion depth changed minimally. In conclusion, geocell measures changed erosion patterns by altering the rill erosion/deposition ratio, converting erosion from rill erosion to sheet erosion.
We reported a patient with unresectable hepatocellular carcinoma (HCC) who initially received 15 cycles of atezolizumab plus bevacizumab combination and had best tumor response of partial response, ...but later experienced disease progression. After subsequent surgical resection, the patient enjoyed long-term disease-free status at the last follow-up 19 months after surgery. By investigating paired tumor tissues (pretreatment and post-progression samples) with immunohistochemistry, multiplex immunofluorescence, RNA sequencing, and DNA sequencing, we explored the dynamic changes in the tumor microenvironment (TME) and potential mechanisms underlying acquired resistance to the combination. In the post-progression HCC tissue compared with the baseline tissue, the expression of PD-L1 in tumor-infiltrating immune cells and the abundance of CD8.sup.+ T cells in the tumor area had decreased, and an immune-excluded TME had emerged. Transcriptomic analysis revealed a gene expression signature representing progenitor/hepatoblast features in the post-progression tumor tissue, with an increased expression of imprinted genes and decreased expression of cytochrome P450 family genes. Finally, tumor mutational burden and MHC class I expression in tumor cells were both increased in the post-progression tissue, suggesting that neoantigen depletion or loss-of-antigen presentation were unlikely causes of acquired resistance in this patient. Atezolizumab plus bevacizumab combination therapy enabled our patient to receive hepatectomy and achieve long-term remission. A comparison of paired tumor tissues suggested that immune-excluded TME and tumor dedifferentiation may have contributed to acquired resistance to the combination. Keywords: Atezolizumab, Bevacizumab, Hepatocellular carcinoma, Immune exclusion, PD-L1
In spring 2018 the SuperKEKB electron-positron collider at High Energy Accelerator Research Organization (KEK, Tsukuba, Japan) will deliver its first collisions to the Belle II experiment. The aim of ...Belle II is to collect a data sample 50 times larger than the previous generation of BFactories taking advantage of the unprecedented SuperKEKB design luminosity of 8×10
35
cm
-2
s
-1
. The Belle II detector will allow to conduct precise measurements in the harsh collider environment, probing for signs of physics beyond the standard model at the precision frontier.
In order to deliver data suitable for physics analysis, the detector has to be properly calibrated on a regular basis. Among other calibrations the detector alignment plays a key role. For example, precise measurements of time dependent CP-violation rely on the accurate alignment of the new vertex detector, as well as on the determination of the beamspot position and size. To automate the calibration procedures and manage the large amount of data and processing power needed for detector calibration, a software framework has been developed which allows to define the complete workflow and to execute it on a computing cluster. The framework integrates the Millepede II algorithm to solve the large minimization problem emerging in the track-based alignment and calibration of the pixel and strip detector, the central drift chamber, and the muon system.
The first collision data will allow to test and to further improve and tune the alignment and calibration procedures. Although the vertexing capabilities will be limited due to the installation of only a small slice of the full vertex detector, the commissioning phase will allow to test most of the alignment procedure features and to prepare for the full operation. We will present the results achieved during the first data taking, the experience gained and the plans for the first physics run with the full detector.
The variability of surface air temperature extremes has been the focus of attention during the past several decades, and may exert a great influence on the global hydrologic cycle and energy balance ...through thermal forcing. Based on daily minimum (TN) and maximum temperature (TX) observed by the China Meteorological Administration at 143 meteorological stations in the Yangtze River Basin (YRB), a suite of temperature indices recommended by the Expert Team on Climate Change Detection and Indices, with a primary focus on extreme events, were computed and analyzed for the period of 1960–2012 for this area. The results show widespread significant changes in all temperature indices associated with warming in the YRB during 1960–2012. On the whole, cold-related indices, i.e., cold nights, cold days, frost days, icing days and cold spell duration index significantly decreased by −3.45, −1.03, −3.04, −0.42 and −1.6days/decade, respectively. In contrast, warm-related indices such as warm nights, warm days, summer days, tropical nights and warm spell duration index significantly increased by 2.95, 1.71, 2.16, 1.05 and 0.73days/decade. Minimum TN, maximum TN, minimum TX and maximum TX increased significantly by 0.42, 0.18, 0.19 and 0.14°C/decade. Because of a faster increase in minimum temperature than maximum temperature, the diurnal temperature range (DTR) exhibited a significant decreasing trend of −0.09°C/decade for the whole YRB during 1960–2012. However, the decreasing trends all occurred in 1960–1985, while increasing trends though insignificant were found in all sub-regions and the whole YRB during 1986–2012. Geographically, stations in the eastern Tibet Plateau and northeastern YRB showed stronger trends in almost all temperature indices. Time series analysis indicated that the YRB was dominated by a general cooling trend before the mid-1980s, but a warming trend afterwards. In general, the overall warming in the YRB was mainly due to the warming in 1986–2012. Strong relationships between temperature trends and elevation were detected in this study. The warming rates increased with elevation when elevation is above 350m, but decreased with elevation when elevation is below 350m.
•This paper provides the most comprehensive analysis of temperature extremes in YRB.•Changes of temperature extremes were analyzed in various regions and time periods.•Increase in DTR was found in all sub-regions and the whole YRB during 1986–2012.•The YRB showed a general cooling trend before mid-1980s but a warming afterwards.•Strong relationships between temperature trends and elevation were detected.
Abstract Background To evaluate the safety and feasibility of singleincision laparoscopic cholecystectomy (SILC) using a novel instrument. Materials and Methods From September 2011 to June 2012, ...eligible patients (150 cases) were divided randomly into three groups: group A, SILC using a novel instrument; group B, SILC using a conventional instrument; and group C, conventional laparoscopic cholecystectomy (LC). Operative and postoperative outcomes were analyzed. Results The operative times for Group A mean 40 minutes; rang 30-50 minutes and Group B mean 37.5 minutes; rang 25-50 minutes demonstrated no significant differences (P=0.610), but both times were longer than that in Group C mean 25 minutes; rang 20-35 minutes (Z=25.165, P=0.000; Z=16.184, P=0.000). There was no significant difference between the level of blood loss in Group A mean 10.0ml; range 5.0-20.0ml and Group B mean 10.0ml; range 5.0-20.0ml (P=0.989), but the level in both groups was higher than that in Group C mean 7.5ml; range 5.0-10.0ml (Z=12.571, P=0.002; Z=13.619, P=0.001). There were no significant differences in patient satisfaction and pain scores (P=0.519; P=0.691) among the three groups. Complications occurred in 4 cases, including 1 case of bile injury and 3 cases of bile leakage. There were no complications in SILC with a novel instrument. Conclusions SILC require a longer operative time and more blood loss without benefit of patient satisfaction and pain scores. However, SILC with a novel instrument has fewer complications and a tendency to safer than SILC with a conservative instrument, and it could be a possible alternative in cholecystectomy.
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