Avoidance of apoptosis is critical for the development and sustained growth of tumours. The pro-survival protein myeloid cell leukemia 1 (MCL1) is overexpressed in many cancers, but the development ...of small molecules targeting this protein that are amenable for clinical testing has been challenging. Here we describe S63845, a small molecule that specifically binds with high affinity to the BH3-binding groove of MCL1. Our mechanistic studies demonstrate that S63845 potently kills MCL1-dependent cancer cells, including multiple myeloma, leukaemia and lymphoma cells, by activating the BAX/BAK-dependent mitochondrial apoptotic pathway. In vivo, S63845 shows potent anti-tumour activity with an acceptable safety margin as a single agent in several cancers. Moreover, MCL1 inhibition, either alone or in combination with other anti-cancer drugs, proved effective against several solid cancer-derived cell lines. These results point towards MCL1 as a target for the treatment of a wide range of tumours.
Historical reanalyses that span more than a century are needed for a wide range of studies, from understanding large‐scale climate trends to diagnosing the impacts of individual historical extreme ...weather events. The Twentieth Century Reanalysis (20CR) Project is an effort to fill this need. It is supported by the National Oceanic and Atmospheric Administration (NOAA), the Cooperative Institute for Research in Environmental Sciences (CIRES), and the U.S. Department of Energy (DOE), and is facilitated by collaboration with the international Atmospheric Circulation Reconstructions over the Earth initiative. 20CR is the first ensemble of sub‐daily global atmospheric conditions spanning over 100 years. This provides a best estimate of the weather at any given place and time as well as an estimate of its confidence and uncertainty. While extremely useful, version 2c of this dataset (20CRv2c) has several significant issues, including inaccurate estimates of confidence and a global sea level pressure bias in the mid‐19th century. These and other issues can reduce its effectiveness for studies at many spatial and temporal scales. Therefore, the 20CR system underwent a series of developments to generate a significant new version of the reanalysis. The version 3 system (NOAA‐CIRES‐DOE 20CRv3) uses upgraded data assimilation methods including an adaptive inflation algorithm; has a newer, higher‐resolution forecast model that specifies dry air mass; and assimilates a larger set of pressure observations. These changes have improved the ensemble‐based estimates of confidence, removed spin‐up effects in the precipitation fields, and diminished the sea‐level pressure bias. Other improvements include more accurate representations of storm intensity, smaller errors, and large‐scale reductions in model bias. The 20CRv3 system is comprehensively reviewed, focusing on the aspects that have ameliorated issues in 20CRv2c. Despite the many improvements, some challenges remain, including a systematic bias in tropical precipitation and time‐varying biases in southern high‐latitude pressure fields.
A significant new version of the Twentieth Century Reanalysis data assimilation system, 20CRv3, has been developed. The 20CRv3 dataset will provide an ensemble of sub‐daily global atmospheric conditions spanning at least 180 years by assimilating only surface pressure observations into a coupled atmosphere–land forecast model. The new 20CRv3 system improves upon the previous system in several notable ways, including the use of upgraded data assimilation methods, a newer and higher‐resolution forecast model, and a larger set of available pressure observations.
To describe pachymetric progression indices (PPI) of the Pentacam HR (Oculus Optikgeräte GmbH) and the concept of relational thickness, and to test their accuracy for differentiating keratoconic and ...normal corneas compared with single-point thickness values.
One hundred thirteen individual eyes randomly selected from 113 normal patients and 44 eyes of 44 patients with keratoconus were studied using the Pentacam HR by acquiring central corneal thickness (CCT), thinnest point (TP), position of the TP and PPI at minimal (PPI Min) and maximal (PPI Max) meridians, and the average (PPI Ave) of all meridians. Relational thickness parameters were calculated as the ratios of TP and CCT and PPI values. Mann-Whitney U test assessed differences in groups for each variable. Receiver operating characteristic (ROC) curves were calculated for all variables and pairwise comparisons were performed.
Statistically significant differences were noted between normal and keratoconic eyes for all parameters (P<.001), except for horizontal position of TP (P=.79). The best parameters, named Ambrósio's Relational Thickness (ART), were ART-Ave (TP/PPI Ave) and ART-Max (TP/PPI Max) with areas under the ROC curves of 0.987 and 0.983, respectively. The best cutoffs were 424 μm and 339 μm for ART-Ave and ART-Max, respectively. Pachymetric progression indices and ART had a greater area under the curve than TP and CCT (P<.001); TP (0.955) had a greater area under the curve than CCT (0.909; P=.002).
Tomographic-derived pachymetric parameters were better able to differentiate normal and keratoconic corneas than single-point pachymetric measurements. Further studies are needed to evaluate the role of tomography in identifying early forms of ectasia as well as ectasia risk among LASIK candidates.
Slaughterhouses are hotspots for the transmission of antimicrobial-resistant pathogens. We conducted stakeholder discussions on antimicrobial-resistant pathogens within the slaughterhouse setting. ...Butchers were described as powerful stakeholders; challenges included limited funding and staff, inadequate infrastructure, and limited laboratory capacity. Slaughterhouse workers understood that their work increased their risk for exposure.
•Sequencing results and cost were compared for three library kits and benchtop sequencers.•Breadth of coverage at genome termini was influenced by library preparation.•The Ion Torrent S5 generates ...more high-quality reads at lower cost than the PGM.•Indels in homopolymer regions were observed in Ion Torrent S5 consensus genomes.•Illumina MiSeq was the least expensive platform for low-throughput runs.
Next-generation sequencing is a powerful tool for virological surveillance. While Illumina® and Ion Torrent® sequencing platforms are used extensively for generating viral RNA genome sequences, there is limited data comparing different platforms. The Illumina MiSeq, Ion Torrent PGM and Ion Torrent S5 platforms were evaluated using a panel of sixteen specimens containing picornaviruses and human caliciviruses (noroviruses and sapoviruses). The specimens were processed, using combinations of three library preparation and five sequencing kits, to assess the quality and completeness of assembled viral genomes, and an estimation of cost per sample to generate the data was calculated. The choice of library preparation kit and sequencing platform was found to impact the breadth of genome coverage and accuracy of consensus viral genomes. The Ion Torrent S5 510 chip runs produced more reads at a lower cost per sample than the highest output Ion Torrent PGM 318 chip run, and generated the highest proportion of reads for enterovirus D68 samples. However, indels at homopolymer regions impacted the accuracy of consensus genome sequences. For lower throughput sequencing runs (i.e., Ion Torrent 510 and Illumina MiSeq Nano V2), the cost per sample was lower on the MiSeq platform, whereas with higher throughput runs (Ion Torrent 530 and Illumina MiSeq V2) there is less of a difference in the cost per sample between the two sequencing platforms ($5.47-$10.25 more per sample for an Ion Torrent 530 chip run when multiplexing 24 samples). These findings suggest that the Ion Torrent S5 and Illumina MiSeq platforms are both viable options for genomic sequencing of RNA viruses, each with specific advantages and tradeoffs.
is a major human pathogen that colonizes the gastric mucosa and plays a causative role in development of peptic ulcers and gastric cancer. Neutrophils are heavily infected with this organism
and play ...a prominent role in tissue destruction and disease. Recently, we demonstrated that
exploits neutrophil plasticity as part of its virulence strategy eliciting N1-like subtype differentiation that is notable for profound nuclear hypersegmentation. We undertook this study to test the hypothesis that hypersegmentation may enhance neutrophil migratory capacity. However, EZ-TAXIScan™ video imaging revealed a previously unappreciated and progressive chemotaxis defect that was apparent prior to hypersegmentation onset. Cell speed and directionality were significantly impaired to fMLF as well as C5a and IL-8. Infected cells oriented normally in chemotactic gradients, but speed and direction were impaired because of a uropod retraction defect that led to cell elongation, nuclear lobe trapping in the contracted rear and progressive narrowing of the leading edge. In contrast, chemotactic receptor abundance, adhesion, phagocytosis and other aspects of cell function were unchanged. At the molecular level,
phenocopied the effects of Blebbistatin as indicated by aberrant accumulation of F-actin and actin spikes at the uropod together with enhanced ROCKII-mediated phosphorylation of myosin IIA regulatory light chains at S19. At the same time, RhoA and ROCKII disappeared from the cell rear and accumulated at the leading edge whereas myosin IIA was enriched at both cell poles. These data suggest that
inhibits the dynamic changes in myosin IIA contractility and front-to-back polarity that are essential for chemotaxis. Taken together, our data advance understanding of PMN plasticity and
pathogenesis.
Defining environmental factors responsible for development of autoimmunity in rheumatoid arthritis (RA) is critical for understanding mechanisms of disease initiation and propagation. Notably, a ...history of cigarette smoking has been implicated in the genesis of RA and is associated with worse disease outcomes. Antibodies to peptidylarginine deiminase 4 (PAD4) are also associated with more severe RA. A subset of patients who have PAD4 autoantibodies that cross-react with PAD3 (anti-PAD3/4) are at the highest risk for interstitial lung disease, and this risk is augmented by a history of cigarette smoking. It is unclear, however, if smoking is etiologically linked to the development of anti-PAD4 antibodies.
Patients were included in this study if they had physician-diagnosed RA as well as DNA, serum, and a date-matched clinical assessment (n = 274). Anti-PAD4 and anti-CCP antibodies were measured by immunoprecipitation and ELISA, respectively; shared epitope (SE) status was determined by HLA-DRβ1 genotyping. Logistic regression analysis was used to evaluate associations of smoking with PAD4 antibodies, with adjustment for relevant demographic and clinical features. Stratified analyses by disease duration and shared epitope status were also performed.
Anti-PAD4 antibodies were present in 25% of RA patients, with 50% of these individuals having anti-PAD3/4 cross-reactive antibodies. Anti-PAD4 antibodies were significantly associated with a longer disease duration, SE alleles, and anti-CCP antibodies. Importantly, there were no significant differences in smoking history between anti-PAD4 positive and negative groups in univariate analyses, stratified analyses, or multivariable models. However, an inverse relationship between smoking and anti-PAD4 antibodies was suggested by a lower prevalence of current smokers among patients with anti-PAD3/4 antibodies compared to antibody negative individuals (p = 0.04). Further, the lowest levels of anti-PAD4 antibodies were observed in current smokers (p = 0.14), and a significant association of SE and anti-PAD4 antibodies was only present among never smokers (p = 0.01).
Smoking history was not associated with anti-PAD4 antibodies in patients with RA. The finding that anti-PAD4 antibodies were not associated with smoking suggests that other environmental factors may contribute to the development of autoimmunity to PAD4 in these patients.
During and after fabrication of polymeric food contact articles (FCA), polymers undergo oxidation by thermal decomposition processes initiated by oxygen, heat, light, shear, and catalyst residues. To ...reduce degradation of the polymer, a commonly used secondary antioxidant (AO), Irgafos 168 (I-168), may be included. Use of I-168 in polymeric FCAs presents a potential concern for neurotoxicity due to its phosphate-containing degradation species, I-168ate. As a result, we evaluated dietary exposure and oral toxicity data for I-168 and its degradants when used as an AO in FCAs. Our exposure assessment included extensive review of the U.S. food-contact regulatory history of I-168 resulting in a combined cumulative estimated daily intake (CEDI) of 0.09 mg/kg bw/day for I-168 and I-168ate when used as an AO in FCAs. Our comprehensive literature review of toxicological data and supporting structure activity relationship (SAR) analysis of I-168 reactivity against acetylcholinesterase diminished concern for potential neurotoxic effects of I-168 and its degradants. An acceptable daily intake (ADI) value of 1 mg/kg bw/day for I-168 was derived from a two-year rodent combined chronic toxicity/carcinogenicity study, which is higher than the CEDI and supports the safety of current authorized food contact use levels of I-168.
•US FDA conducted a post-authorization review for the food contact uses of I-168.•CEDI for I-168 (phosphite and phosphate) is 0.09 mg/kg bw/day.•ADI for I-168 was derived to be 1 mg/kg bw/day, which is above the CEDI.•There is no safety concern for current authorized food contact use levels of I-168.
Sepsis commonly results in elevated serum troponin levels and increased risk for postsepsis cardiovascular complications; however, the association between troponin levels during sepsis and ...cardiovascular complications after sepsis is unclear.
To evaluate the association between serum troponin levels during sepsis and 1 year after sepsis cardiovascular events.
We analyzed adults aged ⩾40 years without preexisting cardiovascular disease within 5 years, admitted with sepsis across 21 hospitals from 2011 to 2017. Peak serum troponin I levels during sepsis were grouped as normal (⩽0.04 ng/ml) or tertiles of abnormal (>0.04 to ⩽0.09 ng/ml, >0.09 to ⩽0.42 ng/ml, or >0.42 ng/ml). Multivariable adjusted cause-specific Cox proportional hazards models with death as a competing risk were used to assess associations between peak troponin I levels and a composite cardiovascular outcome (atherosclerotic cardiovascular disease, atrial fibrillation, and heart failure) in the year following sepsis. Models were adjusted for presepsis and intrasepsis factors considered potential confounders.
Among 14,046 eligible adults with troponin I measured, 2,012 (14.3%) experienced the composite cardiovascular outcome, including 832 (10.9%) patients with normal troponin levels, as compared with 370 (17.3%), 376 (17.6%), and 434 (20.3%) patients within each sequential abnormal troponin tertile, respectively (
< 0.001). Patients within the elevated troponin tertiles had increased risks of adverse cardiovascular events (adjusted hazard ratio aHR
= 1.37; 95% confidence interval CI, 1.20-1.55; aHR
= 1.44; 95% CI, 1.27-1.63; and aHR
= 1.77; 95% CI, 1.56-2.00).
Among patients without preexisting cardiovascular disease, troponin elevation during sepsis identified patients at increased risk for postsepsis cardiovascular complications. Strategies to mitigate cardiovascular complications among this high-risk subset of patients are warranted.
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