Aim
Inflammatory markers such as serum C‐reactive protein (CRP) are used as routine markers to detect anastomotic leakage following colorectal surgery. However, CRP is characterized by a relatively ...low predictive value, emphasizing the need for the development of novel diagnostic approaches. Volatile organic compounds (VOCs) are gaseous metabolic products deriving from all conceivable bodily excrements and reflect (alterations in) the patient's physical status. Therefore, VOCs are increasingly considered as potential non‐invasive diagnostic biomarkers. The aim of this study was to assess the diagnostic accuracy of urinary VOCs for colorectal anastomotic leakage.
Methods
In this explorative multicentre study, urinary VOC profiles of 22 patients with confirmed anastomotic leakage and 27 uneventful control patients following colorectal surgery were analysed by field asymmetric ion mobility spectrometry (FAIMS).
Results
Urinary VOCs of patients with anastomotic leakage could be distinguished from those of control patients with high accuracy: area under the receiver operating characteristics curve 0.91 (95% CI 0.81–1.00, P < 0.001), sensitivity 86% and specificity 93%. Serum CRP was significantly increased in patients with a confirmed anastomotic leak but with lower diagnostic accuracy compared to VOC analysis (area under the receiver operating characteristics curve 0.82, 95% CI 0.68–0.95, P < 0.001). Combining VOCs and CRP did not result in a significant improvement of the diagnostic performance compared to VOCs alone.
Conclusion
Analysis by FAIMS allowed for discrimination between urinary VOC profiles of patients with a confirmed anastomotic leak and control patients following colorectal surgery. A superior accuracy compared to CRP and apparently high specificity was observed, underlining the potential as a non‐invasive biomarker for the detection of colorectal anastomotic leakage.
Huntington's disease (HD) is an inherited, neurodegenerative disorder caused by the expansion of a glutamine repeat in the N-terminus of the huntingtin protein. To gain insight into the pathogenesis ...of HD, we generated transgenic mice that express a cDNA encoding an N-terminal fragment (171 amino acids) of huntingtin with 82, 44 or 18 glutamines. Mice expressing relatively low steady-state levels of N171 huntingtin with 82 glutamine repeats (N171-82Q) develop behavioral abnormalities, including loss of coordination, tremors, hypokinesis and abnormal gait, before dying prematurely. In mice exhibiting these abnormalities, diffuse nuclear labeling, intranuclear inclusions and neuritic aggregates, all immunoreactive with an antibody to the N-terminus (amino acids 1–17) of huntingtin (AP194), were found in multiple populations of neurons. None of these behavioral or pathological phenotypes were seen in mice expressing N171-18Q. These findings are consistent with the idea that N-terminal fragments of huntingtin with a repeat expansion are toxic to neurons, and that N-terminal fragments are prone to form both intranuclear inclusions and neuritic aggregates.
X‐box binding protein‐1 (XBP‐1) is a transcription factor essential for plasma cell differentiation. XBP‐1 transcripts are found at high levels in plasma cells from rheumatoid synovium and myeloma ...cell lines. Lymphoid chimeras deficient in XBP‐1 have a profound defect in plasma cell differentiation, with few plasma cells in their periphery and severely reduced serum immunoglobulin levels. When introduced into B‐lineage cells, XBP‐1 initiates plasma cell differentiation. XBP‐1 is also the mammalian homologue of the yeast transcription factor Hac1p, an important component of the unfolded protein response (UPR). The UPR allows cells to tolerate conditions of endoplasmic reticulum (ER) stress caused by misfolded proteins. Studies examining the relationship between plasma cell differentiation, XBP‐1, and the UPR demonstrate that this novel signaling system is vital for plasma cell differentiation. Signals that induce plasma cell differentiation and the UPR cooperate via XBP‐1 to induce terminal B‐cell differentiation. Additionally, XBP‐1 plays an important role in the regulation of interleukin‐6 production, a cytokine essential for plasma cell survival.
This study evaluated the efficacy and safety of ziv-aflibercept in combination with cisplatin and pemetrexed in non-small cell lung cancer (NSCLC).
This single arm, multicentre phase II trial ...enrolled patients with previously untreated, locally advanced or metastatic non-squamous NSCLC. Patients received intravenous ziv-aflibercept 6 mg kg(-1), pemetrexed 500 mg m(-2), and cisplatin 75 mg m(-2), every 21 days for up to six cycles. Maintenance administration of ziv-aflibercept was to continue until disease progression, intolerable toxicity or other cause for withdrawal. The co-primary end points were objective response rate (ORR) and progression-free survival (PFS). Planned sample size was 72 patients.
The study was closed prematurely because of three confirmed and two suspected cases of reversible posterior leukoencephalopathy syndrome (RPLS). A total of 42 patients were enrolled. Median age was 61.5 years; 55% were male, 86% Caucasian and 50% had Eastern Cooperative Oncology Group performance status (ECOG PS)=0. A median of four cycles of ziv-aflibercept was administered. The most common treatment-emergent adverse events (TEAEs) of any grade were nausea (69%) and fatigue (67%), with hypertension (36%) as the most common grade 3/4 TEAE. Of the 38 evaluable patients, ORR was 26% and median PFS was 5 months.
Cases of RPLS had been observed in other studies in the ziv-aflibercept clinical development programme but the rate observed in this study was higher than previously observed. This might be related to declining renal function and/or hypertension. Although ORR and PFS were in accordance with most historical first-line NSCLC studies, this combination of ziv-aflibercept/cisplatin/pemetrexed will not be further explored in NSCLC.
Human papillomavirus type 16 (HPV16)-E6 antibodies are detectable in peripheral blood before diagnosis in the majority of HPV16-driven oropharyngeal squamous cell carcinoma (OPSCC), but the timing of ...seroconversion is unknown.
We formed the HPV Cancer Cohort Consortium which comprises nine population cohorts from Europe, North America and Australia. In total, 743 incident OPSCC cases and 5814 controls provided at least one pre-diagnostic blood sample, including 111 cases with multiple samples. Median time between first blood collection and OPSCC diagnosis was 11.4years (IQR=6–11years, range=0–40years). Antibodies against HPV16-E6 were measured by multiplex serology (GST fusion protein based Luminex assay).
HPV16-E6 seropositivity was present in 0.4% of controls (22/5814; 95% CI 0.2% to 0.6%) and 26.2% (195/743; 95% CI 23.1% to 29.6%) of OPSCC cases. HPV16-E6 seropositivity increased the odds of OPSCC 98.2-fold (95% CI 62.1–155.4) in whites and 17.2-fold (95% CI 1.7–170.5) in blacks. Seropositivity in cases was more frequent in recent calendar periods, ranging from 21.9% pre-1996 to 68.4% in 2005 onwards, in those with blood collection near diagnosis (lead time <5years). HPV16-E6 seropositivity increased with lead time: 0.0%, 13.5%, 23.7%, and 38.9% with lead times of >30years (N=24), 20–30years (N=148), 10–20years (N=228), and <10years (N=301 cases) (p-trend<0.001). Of the 47 HPV16-E6 seropositive cases with serially-collected blood samples, 17 cases seroconverted during follow-up, with timing ranging from 6 to 28years before diagnosis. For the remaining 30 cases, robust seropositivity was observed up to 25years before diagnosis.
The immune response to HPV16-driven tumorigenesis is most often detectable several decades before OPSCC diagnosis. HPV16-E6 seropositive individuals face increased risk of OPSCC over several decades.
Methane (CH4) emissions from climate‐sensitive ecosystems within the northern permafrost region represent a potentially large but highly uncertain source, with current estimates spanning a factor of ...seven (11–75 Tg CH4 yr−1). Accelerating permafrost thaw threatens significant increases in pan‐Arctic CH4 emissions, amplifying the permafrost carbon feedback. We used airborne imaging spectroscopy with meter‐scale spatial resolution and broad coverage to identify a previously undiscovered CH4 emission hotspot adjacent to a thermokarst lake in interior Alaska. Hotspot emissions were confined to <1% of the 10 ha lake study area. Ground‐based chamber measurements confirmed average daily fluxes from the hotspot of 1,170 mg CH4 m−2 d−1, with extreme daily maxima up to 24,200 mg CH4 m−2 d−1. Ground‐based geophysical measurements revealed thawed permafrost directly beneath the CH4 hotspot, extending to a depth of ∼15 m, indicating that the intense CH4 emissions likely originated from recently thawed permafrost. Hotspot emissions accounted for ∼40% of total diffusive CH4 emissions from the lake study site. Combining study site findings with hotspot statistics from our 70,000 km2 airborne survey across Alaska and northwestern Canada, we estimate that pan‐Arctic terrestrial thermokarst hotspots currently emit 1.1 (0.1–5.2) Tg CH4 yr−1, or roughly 4% of the annual pan‐Arctic wetland budget from just 0.01% of the northern permafrost land area. Our results suggest that significant proportions of pan‐Arctic CH4 emissions originate from disproportionately small areas of previously undetermined thermokarst emissions hotspots, and that pan‐Arctic CH4 emissions may increase non‐linearly as thermokarst processes increase under a warming climate.
Plain Language Summary
We conducted high‐resolution airborne surveys of near‐surface methane (CH4, a powerful greenhouse gas) anomalies in permafrost ecosystems in Alaska and northwestern Canada as part of NASA's Arctic Boreal Vulnerability Experiment (ABoVE). These measurements provided fine‐scale resolution for the remote detection of CH4 emission hotspots from natural Arctic environments. Repeated flights over Big Trail Lake near Fairbanks, AK revealed a previously undiscovered CH4 hotspot at this intensive study site. Ground‐based measurements confirmed extremely high surface‐to‐atmosphere emissions at this location, on the shore of a permafrost‐thaw pond that formed after 1963. Geophysical surveys confirmed the presence of thawed permafrost underneath the hotspot, extending to a depth ∼15 m. We hypothesize that recent permafrost thaw and subsidence made soils with highly decomposable organic carbon available for microbial metabolism, conversion into CH4, and enhanced emission to the atmosphere. Extrapolating our observed hotspot fluxes across the pan‐Arctic, we estimate that thermokarst CH4 hotspots constitute less than 0.01% of the pan‐Arctic land area, but contribute roughly 4% of annual pan‐Arctic wetland emissions. We further hypothesize that Arctic CH4 emissions may grow significantly in the future with anticipated increases in thermokarst across the permafrost landscape.
Key Points
Repeat airborne spectral imaging geolocated a thermokarst methane (CH4) hotspot with ground‐validated emissions >10 g CH4 m−2 d−1
Hotspot CH4 emissions arose from <1% of our 10 ha thermokarst lake study area but comprised ∼40% of the total diffusive emissions
Ground‐based and airborne observations suggest thermokarst hotspots emit roughly 1.1 Tg CH4 yr−1 or 4% of pan‐Arctic wetland CH4 emissions
Synovial sarcoma is a soft tissue malignancy characterized by the fusion of SS18 to either SSX1, SSX2, or SSX4 genes. SS18 and SSX are transcriptional cofactors involved in activation and repression ...of gene transcription, respectively. SS18 interacts with SWI/SNF, whereas SSX associates with the polycomb chromatin remodeling complex. Thus, fusion of these two proteins brings together two opposing effects on gene expression and chromatin structure. Recent studies have shown that a significant number of genes are down-regulated by the SS18-SSX fusion protein and that the clinically applicable histone deacetylase (HDAC) inhibitor romidepsin inhibits synovial sarcoma growth. Therefore, we set out to identify direct targets of SS18-SSX among genes down-regulated in synovial sarcoma and investigated if romidepsin can specifically counteract SS18-SSX-mediated transcriptional dysregulation. Here, we report that the tumor suppressor early growth response 1 (EGR1) is repressed by the SS18-SSX protein through a direct association with the EGR1 promoter. This SS18-SSX binding correlates with trimethylation of Lys(27) of histone H3 (H3K27-M3) and recruitment of polycomb group proteins to this promoter. In addition, we found that romidepsin treatment reverts these modifications and reactivates EGR1 expression in synovial sarcoma cell models. Our data implicate polycomb-mediated epigenetic gene repression as a mechanism of oncogenesis in synovial sarcoma. Furthermore, our work highlights a possible mechanism behind the efficacy of a clinically applicable HDAC inhibitor in synovial sarcoma treatment.
We construct merger trees for galaxies identified in a cosmological hydrodynamic simulation and use them to characterize predicted merger rates as a function of redshift, galaxy mass, and merger mass ...ratio. At z = 0.3, we find a mean rate of 0.054 mergers per galaxy per Gyr above a 1:2 mass ratio threshold for massive galaxies (baryonic mass above 6.4 x 10 super(10)M sub( )), but only 0.018 Gyr super(-1) for lower mass galaxies. The mass ratio distribution is aR super(-1.2 rnerg) for the massive galaxy sample, so high-mass mergers dominate the total merger growth rate. The predicted rates increase rapidly with increasing redshift, and they agree reasonably well with observational estimates. A substantial fraction of galaxies do not experience any resolved mergers during the course of the simulation, and even for the high-mass sample, only 50% of galaxies experience a greater than 1: 4 merger since z = 1. Typical galaxies thus have fairly quiescent merger histories. We assign bulge-to-disk ratios to simulated galaxies by assuming that mergers above a mass ratio threshold R sub(major) convert stellar disks into spheroids. With R sub(major) values of 1: 4, we obtain a fairly good match to the observed dependence of the early-type fraction on galaxy mass. However, the predicted fraction of truly bulge-dominated systems (f sub(bulge) >0.8) is small, and producing a substantial population of bulge-dominated galaxies may require a mechanism that shuts off gas accretion at late times and/or additional processes (besides major mergers) for producing bulges.
Viruses cleave cellular proteins to remodel the host proteome. The study of these cleavages has revealed mechanisms of immune evasion, resource exploitation, and pathogenesis. However, the full ...extent of virus-induced proteolysis in infected cells is unknown, mainly because until recently the technology for a global view of proteolysis within cells was lacking. Here, we report the first comprehensive catalog of proteins cleaved upon enterovirus infection and identify the sites within proteins where the cleavages occur. We employed multiple strategies to confirm protein cleavages and assigned them to one of the two enteroviral proteases. Detailed characterization of one substrate, LSM14A, a p body protein with a role in antiviral immunity, showed that cleavage of this protein disrupts its antiviral function. This study yields a new depth of information about the host interface with a group of viruses that are both important biological tools and significant agents of disease.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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